Premature Ejaculation and Its Association with Serum Testosterone Levels: A Comprehensive Review

Abstract

Premature ejaculation (PE) is the most common form of male sexual dysfunction. Various hormonal and nutritional deficiencies have been implicated in PE, although conflicting data exist. We sought to determine if androgen levels, particularly testosterone, correlate with PE. A comprehensive narrative review was performed by using PubMed. Exclusion criteria included review articles and articles addressing nonandrogenic hormones. Sixty articles met our inclusion criteria and 165 were excluded. Relatively high testosterone levels were associated with PE, including men with specific medical histories (e.g., emotional trauma and infertility). On a molecular level, increased trinucleotide CAG repeats within the androgen receptor gene contributed to the relationship between high testosterone and PE. Elevated fetal androgen exposure was also linked to increased risk of PE, although the data were contradictory. In addition, although not explicitly related to high testosterone, lowering testosterone via various interventions was associated with PE improvement. Conversely, relatively low testosterone was also associated with increased risk of PE, especially when increasing testosterone through medical or surgical treatments helped alleviate PE in both human- and animal-based models. Finally, numerous studies showed no association between testosterone levels and PE, including in patients with normal or low testosterone, concurrent sexual pathologies (e.g., infertility and chronic prostatitis), comorbid chronic diseases, or various nutritional deficiencies or toxicities. The association between testosterone and PE remains controversial. Relatively high and low testosterone both appear to be associated with PE, although strong evidence exists that PE is not affected by testosterone levels. Thus, the physiologic mechanism behind PE is multifactorial and cannot be attributed solely to testosterone levels.

Introduction

Premature ejaculation (PE) is the most common form of male sexual dysfunction.^1,2 Some sources estimate that >25% of patients presenting for treatment of sexual dysfunction have PE.^3,4 PE is defined as ejaculation consistently occurring within 1 min of vaginal penetration, causing great personal distress.^5,6 In patients without PE, normal intravaginal ejaculatory latency time (IELT) ranges from 5 to 20 min.⁷

There are four subtypes of PE (Table 1). Primary/lifelong PE patients experience symptoms from the start of their sexual maturity, while those with secondary/acquired PE develop the disease over the course of their life span. In terms of prevalence within the general population, primary or variable PE appears to be the most common subtype.^4,11 PE may occur in sexually active men of any age. In one study, accounting for all PE subtypes, the mean age of men presenting with PE was the midthirties, although ages ranged from 24 to 52 years.¹¹ Contradictory evidence exists on whether PE increases or decreases in prevalence with increasing age.^4,12

Table 1.

Subtypes of Premature Ejaculation^5,8–10

Subtype of PE	Definition
Primary/lifelong PE	When a patient has experienced PE since beginning sexual activity
Secondary/acquired PE	When a patient develops PE after previously normal ejaculatory latency
Variable/natural variable PE	When a patient experiences PE inconsistently
Subjective PE/premature-like ejaculatory dysfunction	When a patient complains of PE, although the intravaginal ejaculatory latency time is normal

PE, premature ejaculation.

PE is associated with several pathologies, including prostatitis, obesity, smoking, and the presence of multiple comorbidities.^4,13 In addition, numerous hormonal (e.g., leptin, melatonin, thyroid hormone, oxytocin, and prolactin) and nutritional (e.g., folate, vitamin D, magnesium, and nickel) imbalances have been implicated in PE.^14–35 Androgen levels, particularly testosterone, have also been analyzed for their role in ejaculatory physiology and PE.^36,37

Currently, all medications used for PE treatment are considered off-label.^38,39 Standard treatment for all subtypes includes selective serotonin reuptake inhibitors (SSRIs) (e.g., “on-demand” dapoxetine), topical anesthetics, and cognitive-behavioral therapy.^19,40–43 However, certain SSRIs may negatively impact fertility or be too expensive, causing discontinuance.^44,45 In addition, some men experience PE that is refractory to SSRIs.⁴⁶ Several alternative treatments for PE have been explored with mixed results, including phenoxybenzamine, epelsiban, tadalafil, antiandrogen medications, cligosiban, and exercise.^47–52 Although many treatments exist, their beneficial mechanism often proves elusive.⁵³

A better understanding of PE's etiologies will help improve treatment. The objective of this study was to determine the role of androgens, particularly testosterone, in PE.

Methods

A comprehensive narrative review of PE subtypes and androgen levels was performed by using PubMed (Fig. 1). The PubMed literature review occurred from June 7, 2021, through July 2, 2021. Search fields within PubMed were considered, using MESH search terms and Boolean operators for logic syntax. The search query used was as follows: “(androgens OR testosterone OR hormones) AND premature ejaculation.”

FIG. 1.

Formation of narrative review via PubMed literature search.

A single author (R.H.D.) performed the primary literature review. Publications were screened for title and abstract in English or English translation. Articles were reviewed for relevance to testosterone and its effect on PE as well as for scientific merit. In addition, references of excluded articles were reviewed for potential inclusion. The exclusion criteria included review articles and articles addressing nonandrogenic hormones (e.g., leptin and oxytocin).

Once initial articles were screened for inclusion, assessment of each article's relevance was made with consultation from authors J.W.G. and M.L. All disagreements on article inclusion or exclusion were discussed and resolved through consensus. No statistical or data management software was used to conduct this review.

Results

A total of 225 PubMed hits were identified on initial search. After applying the exclusion criteria, 60 articles were included in this review. Conflicting data were found on the association between serum testosterone levels and PE.

Elevated testosterone and its association with PE

Relatively high testosterone levels have been linked to PE (Table 2). Corona et al. analyzed the hormonal differences among men with acquired and lifelong PE compared with those with delayed ejaculation (DE).⁵⁴ The study included 714 patients with PE and 121 with DE. Serum hormone levels, the Structured Interview on Erectile Dysfunction questionnaire, and severity of PE/DE questionnaires were evaluated. Younger patients aged 25–39 with PE were observed to have higher total testosterone (TT) and calculated free testosterone (cFT) (∼5.75 and 1.44 ng/dL, respectively) when compared with patients with DE or patients with neither PE nor DE (p < 0.05 for both variables). In addition, patients with lifelong PE showed statistically higher cFT than those with acquired PE.

Table 2.

High Testosterone Is Associated with Premature Ejaculation

Principle	Sources
High T levels are associated with PE	^{3,7,36,54–59}
Emotional trauma and infertility are associated with high T and PE	^60,61
Increased trinucleotide CAG repeats are associated with high T and PE	^62,63
Tramadol decreases T, potentially alleviating PE	^64,65

T, testosterone.

In 2011, Corona et al. published an updated cohort and confirmed that higher TT levels were associated with increased severity of PE on multivariable analysis (p = 0.001), but they did not specify the PE subtype.³

Another study assessed 439 patients with new-onset erectile dysfunction (ED) and their comorbid sexual conditions, including PE.⁵⁵ Subjects with ED were divided into two groups: >40 and <40 years old. Two important associations were observed. First, men ≤40 years of age with ED had over two times (12.4% vs. 6.2%) the prevalence of PE (p = 0.03). Second, these same patients also displayed higher TT levels than men >40 years old with ED.

A similar study investigated the differences between ED and Peyronie's disease by examining 163 patients with lifelong PE age-matched to 292 patients with ED.⁵⁶ They found lifelong PE patients had higher TT than ED patients (5.38 ± 1.74 ng/mL vs. 4.89 ± 1.69 ng/mL, respectively, p < 0.001) and patients with neither ED nor PE (5.38 ± 1.74 ng/mL vs. 4.85 ± 1.42 ng/mL, respectively, p < 0.001).

Chen et al. confirmed these findings by comparing TT in PE, ED, and DE patients.⁵⁷ Patients with PE had higher TT levels (4.97 ± 1.65 ng/mL) compared with ED (4.34 ± 1.78 ng/mL) and DE patients (4.13 ± 2.11 ng/mL) (p < 0.001 for both comparisons). In addition, elevated TT was noted to be the sole risk factor for PE compared with control patients on multivariable analysis (odds ratio = 1.154 [95% confidence interval 1.02–1.31], p < 0.001]).

Relatively high testosterone was associated with PE in men with specific medical histories (Table 2). One study assessed this phenomenon in a cohort of men with couple infertility.⁶⁰ They examined 244 men with infertility and discovered the prevalence of PE in their cohort was 15.6%, of which 38.5% had primary and 61.5% had secondary PE. A positive association was observed between higher cFT levels and increased premature ejaculation diagnostic tool (PEDT) scores (r = 0.181, p < 0.02).

Another study investigated the psychosocial aspect of PE via a case/control study.⁶¹ Specifically, they evaluated the correlations between emotional traumatization, PE, and testosterone. To measure experienced trauma, the Trauma Symptoms Checklist (TSC-40) was utilized, with higher scores indicating higher levels of traumatic stress. Increased TSC-40 scores were found to be significantly associated with increased PEDT scores (r = 0.84) and increased cFT (r = 0.62). Although both PEDT scores and cFT rose with increasing TSC-40 scores, an analysis was neither performed on the effect of cFT on PEDT scores nor on the specific PE subtypes experienced by patients mentioned. Analysis was performed on TT and PEDT scores, and the result was not significant.

On the molecular level, it is theorized that increased trinucleotide CAG repeats within the androgen receptor gene (ARG) may contribute to the relationship between relatively high testosterone and PE (Table 2). One study assessed the physiologic and ejaculatory effects of CAG repeats within the ARG.⁶² A total of 271 patients with primary/lifelong PE and 155 men without PE were included in this study. Peripheral blood was collected from patients to determine TT and CAG repeats within the ARG from genomic DNA.

Patients with primary PE had greater TT compared with control patients (4.91 ± 1.81 ng/mL vs. 3.8 ± 1.4 ng/mL, p < 0.001). TT was also negatively associated with self-estimated IELT (r = −0.21, p = 0.001). In addition, long CAG repeats (≥26 total) were significantly associated with higher TT than medium (22–25 total) and short (≤21 total) repeats (long: 5.48 ng/mL; medium: 4.23 ng/mL; short: 4.13 ng/mL; p < 0.001). Interestingly, the association between PEDT score and TT was not statistically significant (r = 0.53, p = 0.21).

Another study was performed in diabetic patients with acquired PE.⁶³ It was discovered that diabetic patients with acquired PE had higher TT than nondiabetic subjects without PE (4.76 ± 1.52 ng/mL vs. 3.63 ± 1.26 ng/mL, respectively, p < 0.001). TT was also inversely related to self-estimated IELT (r = −0.024, p = 0.0001). A higher number of CAG repeats were associated with higher testosterone (r = 0.103), higher PEDT scores (r = 0.289), and lower self-estimated IELT (r = −0.168) (p < 0.001 for all three variables).

Although not explicitly related to high testosterone, lowering testosterone may be associated with PE improvement (Table 2). Recent studies suggest that daily and/or precoital tramadol may be effective at treating PE.^66–69 To understand the impact of tramadol on sexual function, Kabbash et al. found a cohort of tramadol-dependent patients (TdP), 20% of whom began taking tramadol for acquired or lifelong PE.⁶⁴ TT was statistically lower in TdP than nondependent men (4.01 ± 1.63 ng/mL vs. 6.74 ± 2.21 ng/mL, respectively, p = 0.001). In addition, TT decreased as tramadol dosage increased (p = 0.002).

These data suggest that the beneficial effect of tramadol on PE may be by lowering TT, especially in those who use it on a daily basis. However, it should be noted that these TdP also had serious sexual side effects from tramadol dependence, such as decreased libido and increased ED.

A similar result was observed in an animal-based study that explored the relationship between tramadol and sexual hormones.⁶⁵ Control rats were administered 9% saline, while treatment rats received tramadol hydrochloride 40 mg/kg three times weekly for 8 weeks. Rats that received tramadol had significantly lower TT than control rats (3.78 ± 0.52 ng/mL vs. 4.21 ± 0.34 ng/mL, respectively, p < 0.05). The treatment group also had significantly increased testicular oxidation and diminished sperm parameters (e.g., decreased count and motility). Although the safety and efficacy of PE treatment with tramadol are controversial, these studies suggest that tramadol may have a beneficial effect on PE by lowering TT.

Decreased testosterone and its association with PE

Relatively low testosterone may be associated with increased risk of PE (Table 3). Several studies have revealed higher levels of PE in patients with low testosterone and specific demographics or comorbidities.^70–72 However, these studies often demonstrate association (e.g., percent of patients with PE and low testosterone) not causation.

Table 3.

Low Testosterone Is Associated with Premature Ejaculation

Patient demographics	Source
Living in Russia's southern climates	⁷⁰
Living in Dhaka City with infertility	⁷¹
Hypogonadotropic hypogonadism	⁷²
Secondary PE	¹¹

PE improved after increased T from treatment (human models)
Fenfluramine for hypogonadotropic hypogonadism	⁷³
TRT for secondary PE	¹¹
Varicocelectomy	⁷⁴

PE improved after increased T from treatment (animal models)
Satureja montana (winter savory)	⁷⁵
Monsonia angustifolia (Geraniaceae)	⁷⁶
Massularia acuminata root	⁷⁷
Black tea brew of Camellia sinensis	⁷⁸
Bulbine natalensis (Baker) stem	⁷⁹

TRT, testosterone replacement therapy.

For example, Tahtali investigated the hormonal parameters of patients with PE subtypes as well as patients' response to testosterone replacement therapy (TRT).¹¹ Of the 171 patients with PE, 48.6% had primary, 32.2% had secondary, 9.3% had variable, and 9.9% had subjective subtypes. Patients with secondary PE had significantly lower TT than other subtypes as well as the lowest IELT (p = 0.001 for both variables). In addition, patients with secondary PE who qualified as testosterone deficient (e.g., TT <2.30 ng/mL) had shorter IELT (p = 0.031) and worse PEDT scores (p = 0.044) compared with those with normal testosterone levels.

Although not explicitly related to low testosterone, increasing serum testosterone may be associated with PE improvement (Table 3). In this same study by Tahtali, patients with secondary PE who qualified as testosterone deficient received TRT and experienced significant increases in both IELT (4.8-fold improvement, p < 0.001) and PEDT scores (p = 0.002).¹¹ Patients with secondary PE who were not testosterone deficient received dapoxetine treatment and experienced significant improvement in IELT (1.8-fold improvement, p < 0.001), but not PEDT scores (p = 0.062).

When the post-treatment improvements were compared between the testosterone and dapoxetine groups, both IELT (p < 0.001) and PEDT scores (p = 0.001) were better in the TRT patients. This study suggests that low serum testosterone may be associated with increased risk of secondary PE and that increasing testosterone may improve symptoms.

A similar result was seen by another study that assessed the sexual and hormonal impact of varicocelectomy in patients with PE.⁷⁴ A total of 129 varicocele patients participated in the study, 73 of whom underwent varicocelectomy (group 1) and 56 of whom were control (group 2). Before surgery, no significant difference existed in PEDT scores or TT. After surgery, the PEDT score for group 1 significantly improved (baseline: 15.56 ± 2.50, 6 months postoperatively: 11.37 ± 4.25, p < 0.001), yet remained the same for group 2 (baseline: 15.89 ± 2.41, 6 months later: 16.21 ± 1.85, p = 0.159).

In addition, TT increased in the varicocelectomy group after treatment (baseline: 331.89 ± 56.85 ng/mL, 6 months postoperatively: 357.97 ± 53.14 ng/mL, p < 0.001), yet remained the same in group 2 (baseline: 341.87 ± 58.92 ng/mL, 6 months later: 335.25 ± 57.11, p = 0.055). Furthermore, of the patients with below-normal TT levels, 62.8% had normalization postoperatively. Although the effect of TT on acquired or primary PE was not directly measured, these data suggest that PE may improve when TT is increased, especially in those with below-normal values. However, it should be noted that both the influence of varicoceles on PE and the influence of varicocelectomy on TT remain controversial.⁸⁰

Animal-based models have also illustrated improved PE symptoms after elevation of testosterone following treatment (Table 3). One study discovered that Satureja montana (winter savory) significantly increased ejaculatory latency (EL) and raised TT in comparison with control rats (p < 0.05 for both variables).⁷⁵

Another study found a similar result with Monsonia angustifolia (Geraniaceae).⁷⁶ In this study, Monsonia angustifolia was compared with sildenafil citrate (positive control) and 1% ethanol in distilled water (negative control). Both Monsonia angustifolia and sildenafil citrate increased EL and TT compared with the negative control (p < 0.05), and there was no significant difference in EL and TT between the two compounds. A similar increase in EL and TT was reported by Yakubu et al. with Massularia acuminata root and with Bulbine natalensis stem compared with sildenafil citrate and negative control animals.^77,79 These studies on homeopathic remedies suggest that increasing TT may aid in treating PE, although human-based models are still needed to confirm these findings.

Testosterone levels are not associated with PE

No association may exist between testosterone levels and PE (Table 4). One study showed that there was no relationship between salivary testosterone levels and ejaculation latency time (Wald χ²[1] = 0.015, p = 0.904) (Jern 2014).⁸¹ Furthermore, the men in this study who ejaculated within 1 min or 1–5 min were discovered to have similar salivary testosterone levels to men who ejaculated >10 min or experienced anejaculation (Wald χ²[1] = 0.047, p = 0.827). Another study reported that 25.3% of patients with congenital adrenal hyperplasia had lifelong PE and varying levels of TT.⁸² However, these varying levels of TT had no effect on sexuality (e.g., risk of PE), satisfaction with sex life, or sexual activity.

Table 4.

Testosterone Is Not Associated with Premature Ejaculation

CAH, congenital adrenal hyperplasia; cFT, calculated free testosterone; ED, erectile dysfunction; EMAS, European Male Aging Study; GB, ginseng berries; IELT, intravaginal ejaculation latency time; IHH, idiopathic hypogonadotropic hypogonadism; KS, Klinefelter syndrome; MetS, metabolic syndrome; NALD, nonalcoholic liver disease; PEDT, premature ejaculation diagnostic tool; ST, salivary testosterone; T2D, type 2 diabetes; TT, total testosterone.

Low testosterone levels were not associated with an increased risk of PE (Table 4). Corona et al. investigated sexual dysfunction and hormonal parameters in those men with Klinefelter syndrome (KS).⁸³ They found that KS men had significantly less TT compared with controls (TT in patients with KS: 1.73 ± 1.04 ng/mL, TT in patients without KS: 4.67 ± 1.85 ng/mL, p < 0.005). However, after adjusting for age, the incidence of lifelong PE between the two groups was not statistically different.

A similar result was seen when comparing patients with metabolic syndrome (MetS) compared with patients without MetS.⁸⁵ In this study, both groups were experiencing couple infertility. Although the TT and cFT levels were lower in those with MetS, the rate of PE was similar between groups (PE in patients with MetS: 22.2%, PE in patients without MetS: 14.4%, p = 0.283). However, this study did not discern PE subtypes within their cohort.

In addition, another study investigated the effect of increasing testosterone levels on acquired PE in patients with low testosterone from idiopathic hypogonadotropic hypogonadism.⁹⁰ After a 2-week treatment with 1 mg/day of anastrozole (an aromatase inhibitor), both TT and cFT levels increased. However, no difference was seen in PE before versus after treatment, suggesting low testosterone was not the cause of PE.

Patients with PE were found to have normal testosterone levels (Table 4). Canat et al. investigated the hormonal profile of patients with either lifelong or acquired PE compared with patients without PE.⁹¹ Although patients with PE had several hormones (e.g., thyroid-stimulating hormone, luteinizing hormone [LH], and prolactin) that were statistically lower compared with the reference population, no difference was seen with TT or cFT. A similar result was observed by another study in which TT and cFT levels were not statistically different between those with and those without lifelong or acquired PE.⁹² However, in this second study, there was also no statistically significant difference in LH, prolactin, or follicle-stimulating hormone (FSH) between the groups.

PE was treated by various interventions that had no effect on testosterone levels (Table 4). One study evaluated the effectiveness of dapoxetine treatment in patients with primary PE.⁹³ Patients were required to take at least 12 “on-demand” tablets of 30 mg dapoxetine. On follow-up, both IELT and PE Arabic index increased after treatment, although testosterone remained unchanged. However, it should be noted that the changes in both IELT and PE Arabic index were minor, although still statistically significant.

Kiliç et al. performed a similar study, testing venlafaxine in patients with PE but did not specify the subtype of PE.⁹⁴ Specifically, they did a randomized, single-blind, placebo-controlled, crossover study in which patients received 75 mg of venlafaxine HCl extended release or placebo pill for 2 weeks, followed by a washout period of 1 week, and a subsequent crossover period for an additional 2 weeks. After treatment with either placebo or venlafaxine, IELT was significantly increased, although the increase was the same for both placebo and venlafaxine. Pre- and post-treatment TT remained unchanged in both groups. Of note, this study used a cutoff of <2 min to define PE, rather than the usual <1 min.

Another study analyzed the effects of ginseng berries (GB) on sexual function, including PE.⁹⁵ Patients who received GB had improved PEDT scores at 4- and 8-week follow-up visits; patients who received placebo did not have improved PEDT scores. However, TT remained unchanged for both groups at both the 4- and 8-week visits.

Testosterone was normal in patients with PE and various sexual pathologies (Table 5). Mazzilli et al. assessed the incidence of ejaculatory dysfunction in infertile men.⁹⁶ They found that 16 out of 3280 had PE (0.5%), although TT was normal in all cases. A similar study also observed that infertile patients were more likely to experience PE compared with fertile couples (PEDT scores were >8 in 12.9% of infertile couples vs. 4.1% of fertile couples, p = 0.036).⁹⁷ However, TT and cFT did not differ significantly between groups.

Table 5.

Normal Testosterone Levels in Patients with Premature Ejaculation and Other Comorbidities

Comorbidity	Sources
Sexual health pathologies
Infertility	^96,97
Erectile dysfunction with chronic prostatitis	⁹⁸
Postorgasmic illness syndrome	⁹⁹
Late-onset hypogonadism with ADAM positive questionnaire	¹⁰⁰

Chronic diseases
Type 1 diabetes	¹⁰¹
Metabolic syndrome	¹⁰²
Advanced chronic kidney disease	¹⁰³
Generalized epilepsy	¹⁰⁴

Psychiatric illnesses
Anxiety	¹⁰⁵
Alcoholism	¹⁰⁶

Miscellaneous pathologies
COVID-19 infection	¹⁰⁷
Restless leg syndrome	¹⁰⁸
Folate deficiency	²⁴
Nickel toxicity	³⁴

ADAM, androgen deficiency in the aging male; COVID-19, coronavirus disease 2019.

One study analyzed hormonal parameters and rates of ED in patients with chronic prostatitis.⁹⁸ They reported that PEDT scores increased in the ED group compared with patients without ED (9.98 ± 4.76 vs. 7.43 ± 4.76, respectively, p = 0.003). However, TT did not differ between patients with or without ED (3.81 ± 1.65 ng/mL vs. 4.37 ± 1.54 ng/mL, respectively, p = 0.056).

Another study evaluated sexual function in men with late-onset hypogonadism.¹⁰⁰ Patients were divided into two groups based on if they had a positive Androgen Deficiency in Aging Males questionnaire (group 1) or negative questionnaire (group 2.) They reported that 38.7% of group 1 had a PEDT score ≥9 compared with only 10.9% of group 2 (p < 0.001), although the mean TT was not statistically different between the groups.

Testosterone was normal in patients with chronic diseases and PE (Table 5). Caruso et al. investigated the sexual effects of type 1 diabetes and found that the prevalence of acquired PE and ED in this population was 13% and 25%, respectively.¹⁰¹ They also observed that age, diabetes duration, and severity of depression all had positive correlations with PEDT score (p < 0.001 for all three variables.) Average TT level for type 1 diabetics was normal (6.81 ± 1.50 ng/mL).

Another study showed that patients with secondary PE had an increased prevalence of MetS compared with a healthy control group (% of MetS patients with acquired PE: 18.9%; % of MetS patients without acquired PE: 10.2%, p = 0.019).¹⁰² The TT between those men with acquired PE and those without was not statistically different (TT in patients with acquired PE: 5.08 ± 1.74 ng/mL vs. 5.03 ± 1.68 ng/mL in those without acquired PE, p = 0.833). It should be noted that the IELT used in this study to define PE was <3 min.

Elbardisi et al. assessed the sexual health of those with advanced chronic kidney disease (ACKD).¹⁰³ They discovered that 88.24% of patients with ACKD had acquired PE and that the incidence of PE was significantly correlated with increased age and ED (p < 0.001 for both variables). The TT level was not a risk factor for PE in this population.

Testosterone was normal in PE patients with various deficiencies or toxicities (Table 5). One study investigated the hormonal and nutritional status of patients presenting with ED, acquired PE, and PE combined with ED.²⁴ Patients with lower folate levels were observed to be at increased risk of ED, PE, and PE combined with ED, although TT levels proved similar between all three groups.

Beshir et al. investigated the hormonal parameters, nickel content, and sexual dysfunction rates in men employed as electroplaters.³⁴ They found that factory workers had increased urinary nickel, LH, FSH, and PE rates compared with controls. However, the TT levels in those exposed and those not exposed were not statistically different. These studies suggest that toxicities and deficiencies unrelated to testosterone may affect PE.

Fetal androgen exposure and its association with PE

Fetal androgen exposure (FAE) and its association with primary PE may be assessed by analyzing second-to-fourth digit (2D:4D) ratios in adult male hands. In adult males, the 2D (index finger) is usually shorter in length than 4D (ring finger), while females have equal 2D and 4D or longer 2D lengths.¹⁰⁹ Thus, the fetal testosterone/estradiol ratio is negatively correlated with 2D:4D in male hands.¹¹⁰ A small 2D:4D ratio is also associated with less CAG trinucleotide repeats in the ARG, representing increased androgen sensitivity.¹¹¹

After determining that patient demographics were similar (e.g., age, body habitus, and TT levels), Bolat et al. found that self-estimated IELT was positively correlated with 2D:4D ratios (right hand: r = 0.258, p = 0.003; left hand: r = 0.240, p = 0.006), demonstrating that IELT was extended if less testosterone exposure occurred in utero.¹¹² Furthermore, PEDT scores had a negative association with digit ratios (right hand: r = −0.363, p = 0.003; left hand: r = −0.238, p = 0.006). Interestingly, adult TT levels were not significantly associated with IELT or PEDT score (r = 0.043, p = 0.624; r = 0.025, p = 0.777, respectively). These data suggest that increased FAE is a risk factor for primary PE.

Another study tested whether the 2D:4D ratio was associated with PE, ED, and/or online sexual compulsivity (OSC).¹¹³ Poor control over ejaculation, an element of PE, was discovered in 5% of pornography-consuming patients. Interestingly, the 2D:4D ratio was determined to not affect ejaculatory control, yet increased OSC was associated with less control over ejaculation. These results contradict the results from Bolat et al., in which a decreased 2D:4D ratio was associated with more severe PE. Therefore, further studies are needed to determine if 2D:4D ratios predict risk of PE.

Investigating FAE by assessing anogenital distance (AGD) is controversial. In men, AGD is 2 × longer than in women.¹¹⁴ Animal and human studies suggest that increased AGD is associated with higher FAE, although the data are inconsistent.^115–117 Toprak et al. surmised that AGD was increased in men with lifelong PE (p = 0.01).¹¹⁸ They also determined a positive correlation between PEDT scores and AGD as well as a negative correlation between IELT and AGD (r = 0.199, p = 0.019; r = −0.185, p = 0.028, respectively). No significant relationship was seen between AGD, PEDT, or IELT and adult TT levels.

A similar study was performed in which patients with PE were noted to have a shorter AGD (p < 0.001).¹¹⁹ The authors concluded that their results were similar to Toprak's results, in that altered AGD was associated with PE. However, to better understand the relationship between PE and FAE, further research is needed to elucidate if AGD is increased or decreased in patients with PE.

Limitations

While 60 publications were selected for inclusion, this study was limited by only capturing articles from one database (PubMed). In addition, many studies included in this review were retrospective in nature with few randomized, controlled trials. Our conclusions are therefore limited by the current quality of published literature. However, many studies included a large number of patients from which to draw meaningful conclusions.

Conclusion

Contemporary evidence for the association between testosterone and PE remains controversial. This may, in part, be due to the large patient heterogeneity and poor PE subtyping within the published literature. In addition, many studies use relative values for determining high versus low testosterone in patients with PE rather than using laboratory-based testosterone ranges. This makes it difficult to determine a specific value that would qualify as low or high testosterone when assessing risk for PE.

Currently, relatively high serum testosterone appears to be associated with increased risk of PE. This may be linked to a genetic alteration in ARG, but research into this connection is still developing. Relatively low testosterone appears to only be minimally associated with PE in select patient populations. However, low testosterone is clinically known to profoundly affect erectile health and libido. Therefore, it is reasonable to infer that decreased testosterone may disrupt erectile function, leading to PE. In addition, a strong association did exist between increased relatively low values of testosterone via treatment (e.g., TRT and fenfluramine) and improved PE.

Numerous studies showed that testosterone may not be related to PE risk or treatment. FAE and its association with PE are still underdeveloped, although an association may exist. Thus, the physiologic mechanism underlying PE is multifactorial and cannot be attributed solely to testosterone levels.

Further studies using laboratory-based testosterone ranges are needed to assess if low versus high testosterone is truly related to PE. In addition, large multicentered prospective studies into the treatment of relatively low and high testosterone are needed to fully assess the utility of androgen modulation in PE patients.

We recommend that, at the discretion of each health care provider, measuring serum testosterone levels and other hormone panels may be useful in PE patients. Evaluating serum testosterone may be especially beneficial in patients with PE refractory to standard treatments. In several studies, patients with low testosterone and PE showed improvement in symptoms after TRT. In addition, patients with high testosterone showed improved PE after various testosterone-lowering treatments (e.g., tramadol). Thus, after taking testosterone levels into account, select patients should be counseled on a case-by-case basis for possible testosterone-altering PE therapies.

Footnotes

Authors' Contributions

Conception and design: R.H.D., J.W.G., M.L., and W.J.G.H. Acquisition and analysis of data: R.H.D., J.W.G., and M.L. Writing—original draft: R.H.D., J.W.G., M.L., and W.J.G.H. Writing—revision: J.W.G. and R.H.D. Final approval: R.H.D., J.W.G., M.L., and W.J.G.H.

Acknowledgment

The authors would like to thank Dr. Scott Bailey for editing this manuscript.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Abbreviations Used

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