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Published in final edited form as: Andrologia. 2019 Jul 17;51(9):e13345. doi: 10.1111/and.13345

The association between elevated serum estradiol levels and clinically significant erectile dysfunction in men presenting for andrological evaluation

Kyle B Zuniga 1, Ezra J Margolin 2, Adam De Fazio 3, Anika Ackerman 2, Peter J Stahl 2
PMCID: PMC6903694  NIHMSID: NIHMS1044120  PMID: 31317572

Abstract

The goal of this study was to investigate the association between serum estradiol levels and clinically significant erectile dysfunction in a cohort of men presenting for andrological evaluation. Retrospective review was conducted of patients that presented to a urologist with practice in andrology over an 18-month period. Patients completed the Male Sexual Health Questionnaire and had serum total testosterone and estradiol measurements prior to 10:30 AM via immunoassay. T-tests, chi-square tests, and multivariate logistic regression was used to compare clinical characteristics between those with adequate erectile function (erection scale score >2) versus clinically significant erectile dysfunction (erection scale score ≤ 2). Among 256 patients, average age was 49 years (SD 15), average serum estradiol was 22.3 pg/ml (SD 10.6), and average serum total testosterone was 465.9 pg/ml (SD 206.3). On multivariate logistic regression, serum estradiol was associated with clinically significant erectile dysfunction (OR 1.52 per SD increase, 95% CI 1.11–2.09, p = 0.009) when controlling for serum total testosterone, age, body mass index, and smoking status. These results warrant future studies on the utility of measuring serum estradiol in patients with erectile dysfunction and the use of aromatase inhibitors in patients with erectile dysfunction and elevated serum estradiol.

Keywords: Erectile dysfunction, Estrogen, Estradiol, Male Sexual Dysfunction, Male Sexual Health Questionnaire

INTRODUCTION

Male sexual dysfunction, which includes disorders of erectile function, ejaculatory function, and sexual desire, is a troublingly prevalent phenomenon (McCabe et al., 2016). The number of men suffering from erectile dysfunction (ED), defined by the Fourth International Consultation on Sexual Medicine (ICSM) as “consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual satisfaction,” has reached staggering numbers, with estimates as high as 152 million men worldwide (Aytaç et al., 1999; McCabe et al., 2016; McKinlay, 2000). Furthermore, those numbers are projected to grow to as high as 322 million by 2025 (Aytaç et al., 1999). Disruption of sexual function can result in diminished quality of life, poor sexual relationships, and symptoms of depression (McCabe et al., 2014). Many factors contributing to ED have been identified, including comorbidities like cardiovascular disease, metabolic syndrome, and diabetes mellitus; lifestyle factors such as low physical activity and smoking; and iatrogenic causes such as opiate use and radical prostatectomy (Allen et al., 2018; Besiroglu et al., 2015; Donovan et al., 2016; Feldman et al., 1994; Jackson et al., 2010; Zhao et al., 2017).

A significant amount of research has also gone into understanding the endocrinologic contributors to male sexual function. Testosterone has been shown to be an important hormone for many aspects of sexual health; however, its effect on erectile function, especially in older men, is inconsistent (Bolona et al., 2007; O’Connor et al., 2011; Podlasek et al., 2016). Still, the American Urological Association recommends assessment of serum testosterone in all men with ED, and testosterone replacement therapy improves libido and erectile function in hypogonadal men (Bolona et al., 2007; Montague Drogo et al., 2005). Estrogen is another steroid hormone that may play a role in male sexual function. Converted from androgens by aromatase, estrogen modulates testosterone levels by inhibiting the release of gonadotropin releasing hormone (GnRH) from the hypothalamus which subsequently reduces levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thus reducing testicular testosterone production (Charlesworth et al., 1986; Santen, 1975).

The role that estrogens play in male sexual function remains unclear, and studies reporting on the impact of estrogens on erectile function have been inconsistent (Castello-Porcar et al., 2016; Wu et al., 2016). One study reported that age but not testosterone/estradiol (E2) imbalance was associated with ED (Castello-Porcar et al., 2016). Another study reported conflicting results, stating that serum E2 levels in excess of serum total testosterone (TT) may preclude proper erectile function (Wu et al., 2016). Furthermore, obesity has been shown to be associated with impaired spermatogenesis and erectile function, which may be secondary to increased peripheral aromatization of testosterone to estrogen (El Salam, 2018). This postulate has been further supported in a meta-analysis that reported increased TT levels, reduced serum E2 levels, and improved erectile function after patients underwent bariatric surgery (Lee et al., 2019). Given the inconsistent reports on the effect of serum E2 on erectile function, an exploratory analysis in men presenting for andrological evaluation was performed to determine whether elevated serum E2 may contribute to clinically significant ED.

MATERIALS AND METHODS

Study population

Following institutional review board approval, the electronic medical records was performed of all patients consecutively presenting to a urologist specialized in male reproductive and sexual disorders over an 18-month period. Male patients 18 years of age or older with available Male Sexual Health Questionnaire (MSHQ) scores and serum E2 and TT measurements within 90 days of MSHQ completion were included. All serum E2 and TT measurements were performed via immunoassay and drawn prior to 10:30am. Patients with diagnosis of Peyronie’s disease or those who had undergone radical prostatectomy, pelvic radiation therapy, or inflatable penile prosthesis placement were excluded. The requirement for written patient consent was waived due to the retrospective design of the study.

MSHQ for defining poor erectile function

The MSHQ is a validated, self-administered, 25-question survey used to assess five domains of male sexual function: erectile function, ejaculatory function, libido, sexual satisfaction, and sexual activity (Rosen et al., 2004). It was designed to be culturally sensitive and age appropriate. Responses to each question of the MSHQ are either on a 6-point (0–5) or a 5-point (1–5) scale, with a higher score indicating a higher level of function. Patients were considered to have clinically significant ED if the average score of responses to those items within the “erection scale” domain (MSHQ-es) was two points or less. Those with average MSHQ-es above two points were considered to have adequate erectile function, and these patients served as the control group. This cutoff was based on both the content of the possible responses as well as on MSHQ cutoffs in prior literature (El-Assmy et al., 2015).

Statistical analysis

In order to correct for the effect of outliers, mean serum E2 was calculated of the 268 patients that met inclusion criteria, those subjects whose serum E2 was ≥2 standard deviations (SDs) away from the mean were excluded. The sociodemographic and clinical characteristics of the two groups were compared using t-tests and chi-square tests. Univariate and multivariate logistic regression analyses were used to determine the effect of patient clinical characteristics on the odds of having clinically significant ED. Serum E2 and TT were converted to standardized variables so that the reported odds ratio (OR) represents the increased odds of clinically significant ED per SD increase in E2 or TT.

A locally weighted scatter-plot smoother (LOWESS) was generated using serum E2 and MSHQ-es scores, and the point at which the LOWESS curve began to slope downward was used as a cutoff point for predicting incidence of clinically significant ED. A chi-square analysis was used to compare the proportion of patients with serum E2 levels above the cutoff point in each group. STATA®, version 15 was used for statistical analysis, and p-values below 0.05 were considered statistically significant.

RESULTS

Characteristics of the study population

Of the 785 patients presenting to the clinic within the 18-month study period who completed an MSHQ, 268 patients met our inclusion criteria. 12 of these patients had serum E2 levels greater than 2 SDs above the mean and were excluded from the analysis, resulting in a study sample of 256 patients. The average age of the study sample was 49 years (SD 15). Average serum E2 was 22.3 pg/ml (SD 10.6) and average serum TT was 465.9 pg/ml (SD 206.3). Full characteristics of the study sample can be seen in Table 1.

Table 1:

Characteristics of the overall study cohort and characteristics of the groups with and without clinically significant ED.

Overall,
n = 256		 Adequate
erectile
function
(MSHQ-es >2),
n = 118		 Clinically
significant ED
(MSHQ-es < 2),
n = 138		 p-value
Age in years, mean (SD) 49 (15) 43 (13) 55 (14) p < 0.001
Race, n (%)
   White 99 (38.7) 43 (36.4) 56 (40.6) p = 0.514
   Black 27 (10.6) 10 (8.5) 17 (12.3)
   Asian 4 (1.6) 2 (1.7) 2 (1.5)
   Other 14 (5.5) 9 (7.6) 5 (3.6)
   Unknown/declined 112 (43.8) 54 (45.8) 58 (42.0)
BMI (kg/m2), mean (SD) 27.6 (4.9) 27.0 (4.9) 28.1 (4.9) p = 0.074
Current smoker, n (%) 14 (5.5) 5 (4.2) 9 (6.6) p = 0.407
E2 (pg/ml), mean (SD) 22.3 (10.6) 20.7 (9.5) 23.6 (11.4) p = 0.029
TT (pg/ml), mean (SD) 465.9 (206.3) 482.6 (225.5) 451.6 (206.3) p = 0.232
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Predictors of clinically significant ED

Compared to those with adequate erectile function, those with clinically significant ED tended to be older (55 years SD 14 versus 42 years SD 13, p < 0.001). Higher BMI also trended toward statistical significance (28.1 kg/m2 SD 4.9 versus 27.0 kg/m2 SD 4.9, p = 0.074). Higher serum E2 was also statistically significantly associated with clinically significant ED (23.6 pg/ml SD 11.4 versus 20.7 pg/ml SD 9.5, p = 0.029). Race, smoking status, and serum TT was not statistically significantly different between groups. Full results can be seen in Table 1.

On univariate analysis, age (OR 1.07, 95% CI 1.05–1.10, p < 0.001) and serum E2 (OR 1.33 per SD increase, 95% CI 1.03–1.72, p = 0.031) were statistically significantly associated with a higher odds of clinically significant ED. In the full multivariate analysis accounting for serum E2, serum TT, age, BMI, and smoking status, age (OR 1.08, 95% CI 1.05–1.10, p < 0.001) and serum E2 (OR 1.52 per SD increase, 95% 1.11–2.09, p = 0.009) remained statistically significant. The full results of the logistic regression analysis can be seen in Table 2.

Table 2:

Univariate and multivariate logistic regression analyses for predicting odds of clinically significant erectile dysfunction.

Univariate
logistic
regression		 Multivariate logistic regression
OR (95% CI) OR (95% CI)b OR (95% CI)b OR (95% CI)c
Serum E2a 1.33 (1.03–1.72)* 1.51 (1.12–2.04)** - 1.52 (1.11–2.09)**
Serum TTa 0.86 (0.67–1.10) - 1.11 (0.83–1.48) 0.98 (0.71–1.35)
Age 1.07 (1.05–1.10)*** 1.08 (1.06–1.10)*** 1.08 (1.05–1.10)*** 1.08 (1.05–1.10)***
BMI 1.05 (1.00–1.10) 1.02 (0.96–1.08) 1.04 (0.98–1.10) 1.02 (0.96–1.08)
Smoking Status 1.60 (0.52–4.92) 1.76 (0.53–5.89) 1.86 (0.55–6.30) 1.76 (0.53–5.88)
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*

p <0.05

**

p <0.01

***

p <0.001

a

Converted to normal values for analysis. OR represents odds of clinically significant erectile dysfunction with each standard deviation increase

b

Model includes either serum E2 or serum TT and age, BMI, and smoking status

c

Model includes serum E2, serum TT, age, BMI, and smoking status

Determining a serum E2 cutoff point

A LOWESS regression curve modeling the relationship between serum E2 level and MSHQ-es demonstrates a sharp downward inflection point at serum E2 level slightly above 32 pg/mL (Figure 1). Therefore, 32 pg/mL was chosen as a cut-off point to define an E2 level that negatively impacts erectile function. 42 patients had a high serum E2 level (>32 pg/ml) and 214 patients had a low serum E2 level. A higher proportion of those with a high serum E2 level had clinically significant ED (30.2% versus 9.3%, p = 0.002).

Figure 1:

Figure 1:

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Relationship between serum E2 and MSHQ-es score using a regression curve modeled using locally weighted scatter-plot smoother (LOWESS curve).

DISCUSSION

In this exploratory analysis, serum E2 was statistically significantly associated with increased odds of clinically significant ED independent of serum TT, age, BMI, and smoking status. The possible mechanism behind this is not entirely clear. A small study by Mancini et al. found that serum E2 was associated with a greater degree of ED secondary to venous leakage (Mancini et al., 2005). O’connor et al. similarly investigated the effect of serum E2, and although they found that serum E2 had an association with sexual function distress, they found no association in any domain of sexual function. They suggested that serum E2 was important for male sexual function, but more in the psychological components rather than physiologic (O’Connor et al., 2011). Basar et al. supported this argument, reporting that serum E2 was associated with increased aging symptoms per the Aging Male Symptom (AMS) scale but found no significant association with sexual dysfunction (Basar et al., 2005).

As expected, age was also associated with clinically significant ED. However, serum TT did not appear to be associated. Ahn et al. demonstrated a similar lack of association between serum TT and sexual function (Ahn et al., 2002). A critique of this study is that it may have been underpowered due to the low sample size (n = 213), and this same critique can be made of this analysis. O’connor et al. had a much larger sample size (n = 2830), and they found that serum TT was in fact associated with overall sexual function when adjusting for age, smoking, BMI, and serum E2. Still, the association they observed was modest (O’Connor et al., 2011). BMI did not quite reach statistical significance in its association with poor erectile function on multivariate analysis; however, this may be due to inadequate sample size or its potential correlation with age and serum E2. The association between BMI and serum E2 is well-established (El Salam, 2018; Jasuja et al., 2013). Furthermore, estrogen has been reported to mediate the association between BMI and other pathologies (Fejes et al., 2006; Iyengar et al., 2019; Key et al., 2003). For example, Key et al. reported an association between BMI and breast cancer which was subsequently lost when adjusting for free estradiol (Key et al., 2003). Iyengar et al. reported an association between whole-body fat percentage and invasive breast cancer, with a particularly high magnitude risk of estrogen receptor-positive breast cancer (Iyengar et al., 2019). It was also surprising that smoking status was not statistically significantly associated with poor erectile function, but this may be due the small number of smokers in the study population (n = 14).

A strength of this study was the investigation of the individual effects of serum TT and serum E2 independent of one another. Prior studies in humans have reported conflicting effects of the testosterone:estrogen ratio (Castello-Porcar et al., 2016; Wu et al., 2016). In animal studies, one group found that rabbits chronically treated with serum E2 and phytoestrogens had significantly reduced serum TT levels, and relaxant response of the corpora cavernosum to acetylcholine, nitroglycerine, and nitrergic transmission were significantly reduced compared to the control response (Srilatha et al., 2004). Another murine model study demonstrated that estrogen:testosterone ratio elevation resulted in negative effects on both physiologic and behavioral sexual responses including prolongation of mount, intromission, and ejaculation latency (Adaikan et al., 2003). Although these findings are consistent with knowledge of the regulatory effect that estrogen has on testosterone levels, these studies do not address the effect of estrogen alone.

Based on the results of this analysis, there may be a threshold level of serum E2 at 32 pg/mL, above which erectile function is negatively affected. The results of this analysis may have future implications on the routine testing and management of men presenting with sexual dysfunction. Perhaps control of estrogen levels with treatments such as aromatase inhibitors could be an important aspect of management. Along these lines, an important consideration is the variability between testosterone aromatization to estrogen between individuals. For example, in obese men with excessive amounts of adipose tissue, there is increased aromatization of testosterone. Thus, even in the presence of similar testosterone concentrations, men may have variable estrogen levels due to increased or decreased aromatase activity (Matsumoto, 2013). Owing to this variability and recognized consequences of hormonal imbalance, it may then be clinically useful to monitor serum E2 levels during testosterone replacement therapy in addition to at the time of diagnostic evaluation. Higher power studies with a greater number of patients may produce a more accurate, generalizable cutoff level resulting in clinically significant ED.

Although estrogen in excess may be detrimental for male sexual function, the importance of maintaining estrogen at appropriate levels cannot be discounted. It is understood that estrogen is important in normal development and function of multiple body systems, including the brain, heart, and bones, but estrogen has also been shown to play a key role in healthy male sexual function (Cooke et al., 2017). Carani et al. found that sexual function was restored in a man with aromatase deficiency following treatment with estrogen (Carani et al., 1999). Carani et al. also reported that sex drive was restored in another man with aromatase deficiency and hypogonadism when both testosterone and estrogen levels were returned to the normal range (Carani et al., 2005). Finkelstein et al. conducted a study in which men were split into 2 groups and treated with goserelin acetate to induce experimental gonadotropin deficiency. Normal serum testosterone levels were then restored by administration of testosterone replacement therapy, but in half of the patients, anastrazole was used to block aromatization of testosterone to estrogen. The cohort of men receiving both testosterone and anastrazole had poorer erectile function and sexual desire than men who received testosterone therapy alone, suggesting that estrogens do play a physiologic role in healthy erectile function and sexual desire (Finkelstein et al., 2013).

Although these findings could have implications on future management strategies of men with ED, some significant limitations need to be addressed. An obvious limitation is that the sample is among patients presenting to a urology practice specializing in male reproductive and sexual disorders in a large metropolitan area, which limits the generalizability of the findings. Still, the results of this exploratory analysis indicate that future studies exploring the role of serum E2 monitoring in the management of ED as well as the use of aromatase inhibitor therapy in those with elevated serum E2 levels are warranted. In addition, the small sampling of retrospective data may account for the lack of other significant findings and may introduce other forms of inherent bias. Furthermore, our assessment of sexual dysfunction is purely based in surveys gathering the subjective experience of patients rather than objective measurements of physiologic function. Despite the study’s weaknesses, it surely indicates the importance of further investigation on the independent effects of estrogen on male sexual function.

CONCLUSIONS

Among this cohort of men presenting for andrological evaluation, age and elevated serum E2 were associated with clinically significant ED, and this association remained statistically significant when additionally controlling for serum TT, BMI, and smoking status. Serum TT, BMI, and smoking status were not individually associated with clinically significant ED in this cohort. Statistical analysis of the sample suggested that a serum E2 cutoff of 32 pg/ml may be appropriate when classifying men by E2 status. Future studies exploring the relationship of serum E2 with erectile function are warranted. This study suggests a potential future for treatments that target serum E2 metabolism or signaling, such as aromatase inhibitors, in the clinical care of men with ED.

ACKNOWLEDGEMENTS

This study was funded in part by the National Center for Complementary and Integrative Health, T32AT003997.

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