Erectile [Dys]Function

[Michael Scally MD]

[OA] Brain Aromatase and the Regulation of Sexual Activity in Male Mice

The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol in the testis and brain of male mice.

Estradiol formation was shown to regulate sexual activity in various species, but the relative contributions to sexual behavior of estrogen that arises in the brain versus from the gonads remained unclear.

To determine the role of brain aromatase in regulating male sexual activity, we generated a brain-specific aromatase knockout (bArKO) mouse. A newly generated whole-body total aromatase knockout mouse of the same genetic background served as a positive control.

Here we demonstrate that local aromatase expression and estrogen production in the brain is partially required for male sexual behavior and sex hormone homeostasis.

Male bArKO mice exhibited decreased sexual activity in the presence of strikingly elevated circulating testosterone. In castrated adult bArKO mice, administration of testosterone only partially restored sexual behavior; full sexual behavior, however, was achieved only when both estradiol and testosterone were administered together.

Thus, aromatase in the brain is, in part, necessary for testosterone-dependent male sexual activity. We also found that brain aromatase is required for negative feedback regulation of circulating testosterone of testicular origin.

Our findings suggest testosterone activates male sexual behavior in part via conversion to estradiol in the brain. These studies provide foundational evidence that sexual behavior may be modified through inhibition or enhancement of brain aromatase enzyme activity and/or utilization of selective estrogen receptor modulators.

Brooks DC, Coon V JS, Ercan CM, et al. Brain Aromatase and the Regulation of Sexual Activity in Male Mice. Endocrinology 2020;161. Brain Aromatase and the Regulation of Sexual Activity in Male Mice

 

[Michael Scally MD]

Circadian Rhythm and Erectile Function: Is There A Penile Clock?

Disruption of the circadian clock has been associated with pathological conditions including obesity, type 2 diabetes mellitus, cancer, depression and neurodegenerative diseases. Disturbed sleep patterns have now been associated with reduced erectile function. The mechanisms behind this effect are unclear but could include hypoxia signalling and low testosterone.

Vignozzi, L., Maggi, M. Circadian rhythm and erectile function: is there a penile clock?. Nat Rev Urol (2020). https://doi.org/10.1038/s41585-020-00376-7

 

[Michael Scally MD]

Estradiol Correlates with Erectile Dysfunction and Its Severity in Type 2 Diabetic Patients

Highlights
· Estrogen levels are correlated with erectile function in patients with type 2 diabetes.
· In diabetic patients, hyperestrogenism is a risk factor for severe erectile dysfunction.
· High estrogen levels may impair penile cavernous arterial flow independently of other cardiovascular risk factors.

Aims: Erectile dysfunction (ED) is a frequent microvascular complication of type 2 diabetes mellitus (T2DM). Hormonal derangements such as hypogonadism and hyperestrogenism are common in T2DM. Our aim was to investigate the relationship between estrogens and ED in diabetic patients.

Methods: We performed a retrospective study on 57 patients with T2DM suffering from ED. ED was assessed with the International Index of Erectile Function questionnaire (IIEF-5) and penile color-doppler ultrasound (PCDU). Blood tests included glycated hemoglobin, lipid profile, total testosterone (T), and estradiol (E2).

Results: E2 was negatively correlated with IIEF-5 score after correction for age, diabetes duration, BMI, HbA1c, LDL- and HDL-cholesterol, T and PSA (r = -0.457, p < 0.01). Patients in the higher E2 quartile, had statistically higher probability of severe ED (61.5%). In the same patients, the PCDU demonstrated a statistically longer Acceleration Time (120.0 ± 24.5, p = 0.048) indicating an impaired arterial flow.

Conclusions: In diabetic patients, higher E2 is associated with worse erectile function and impaired cavernous arterial flow. Diabetic patients with high E2 are more prone to severe ED. It could be suggested to include estradiol measurement in the hormonal assessment of ED in patients with T2DM.

De Rocco Ponce M, Garolla A, Caretta N, De Toni L, Avogaro A, Foresta C. Estradiol correlates with erectile dysfunction and its severity in type 2 diabetic patients. J Diabetes Complications. 2020 Sep 6:107728. doi: 10.1016/j.jdiacomp.2020.107728. Epub ahead of print. PMID: 33028498. https://www.sciencedirect.com/science/article/abs/pii/S1056872720305067?via%3Dihub

 

[Michael Scally MD]

 

[Michael Scally MD]

Erectile Dysfunction in Young Men: Testosterone, Androgenic Polymorphisms, and Comorbidity With Premature Ejaculation Symptoms

Background - The association between erectile dysfunction (ED), free testosterone (T), and androgenic genetic polymorphisms is still unclear. As most studies in the field have focused on older (>40 y.o.) men, data from young men is scarce. In addition, the clinically observed comorbidity between ED and premature ejaculation (PE) has not been explained.

Aim - The aim of the present study was 3-fold: to assess in a sample of young men (1) the association between ED and T; (2) the role of androgenic genetic polymorphisms in the aforementioned association; and (3) comorbidity between ED and PE symptoms.

Methods - Statistical analyses were performed on a population-based sample of 2,302 Finnish men, (M age = 26.8 years). Hormone samples were available from 317 men, and genotype information was available from a minimum of 1,144 men depending on genetic locus. For twin analyses, the sample contained 533 male individuals from opposite-sex fraternal twin pairs, 491 identical male individuals (110 complete pairs), 493 male individuals from male fraternal twin pairs (92 complete pairs), and 658 siblings of twins.

Outcomes - The main outcome measure includes association between levels of salivary T and ED, main effects of the androgen-related genetic polymorphisms on ED scores. Bivariate twin models of PE and ED were fitted to elucidate possible shared etiology.

Results - We found no significant association between T levels and ED and no significant main effects of the androgenic genetic polymorphisms on ED. We found no evidence suggesting that any of the genetic polymorphisms would moderate the association between T and ED symptoms. We found shared unique environmental influences between PE and ED ( r E = .28).

Clinical Translation - Obtained data suggest that ED has T-independent causes and that any comorbidity between PE and ED is not explained by a set of genes affecting both phenotypes.

Strengths & Limitations - First, the sample size for both parts of the study was relatively small, which may make some statistical analyses underpowered. Furthermore, as the sample was a population-based sample of relatively young men, the number of clinically relevant ED cases was low. Second, some concerns about T derived from saliva exist because saliva sampling comes with increased risks of error particularly because saliva samples are more vulnerable to contamination.

Conclusion - We found no significant association between free T levels, androgenic genetic polymorphisms, and ED in the younger age cohort. Twin analysis suggested a common nonshared environmental component in PE and ED.

Zhuravleva ZD, Johansson A, Jern P. Erectile Dysfunction in Young Men: Testosterone, Androgenic Polymorphisms, and Comorbidity With Premature Ejaculation Symptoms. The Journal of Sexual Medicine. Redirecting

 

[Michael Scally MD]

[OA] Thinking About Pathomechanisms and Current Treatment of Erectile Dysfunction-"The Stanley Beamish Problem."

Introduction: Up to 50% of all men over 50 years of age suffer from erectile dysfunction. Since the late 1990s erectile dysfunction has been treated mostly with phosphodiesterase 5 inhibitors (PDE5I). Over the past 20 years, numerous scientific findings on the development of erectile dysfunction have been collected, which have so far received little attention in the treatment of erectile dysfunction.

Objectives: The objectives of this study were to review the existing medical literature on erectile dysfunction regarding physiology, pathophysiology, and especially therapeutic options beyond treatment with PDE5I and to enable a more effective and especially sustainable treatment for erectile dysfunction.

Methods: A literature review was performed by using PubMed from 1985 to 2020 regarding the physiology, pathophysiology, and treatment of erectile dysfunction.

Results: Since the end of the 1990s an enormous amount of knowledge has been gained about the physiology/pathophysiology of erection/erectile dysfunction. Based on these findings, numerous physical, drug, and holistic therapeutic options (beyond the application of PDE5I) have been developed for the treatment of erectile dysfunction. However, these are still relatively rarely used in the therapeutic concept of erectile dysfunction today.

Conclusion: Based on scientific findings of the last 20 years, there are numerous therapeutic approaches, including lifestyle modification, specific pelvic floor exercises, shock wave treatment, and the application of different supplements. The long-term treatment of erectile dysfunction should now go beyond the purely symptomatic use of PDE5I.

Beecken WD, Kersting M, Kunert W, et al. Thinking About Pathomechanisms and Current Treatment of Erectile Dysfunction-"The Stanley Beamish Problem." Review, Recommendations, and Proposals. Sex Med Rev. 2020 Dec 23:S2050-0521(20)30120-7. doi: 10.1016/j.sxmr.2020.11.004. Epub ahead of print. PMID: 33358577. https://www.sciencedirect.com/science/article/pii/S2050052120301207?via%3Dihub