In a recent study published in BMJresearchers performed a randomization analysis of two Mendelian samples to investigate the associations between genetically appreciable (via a surrogate biomarker) suppression of phosphodiesterase 5 (PDE5), a recognized pharmacologic target for erectile dysfunction, fertility, subjective well-being, and sexual behavior.
Record
Fertility is declining in many nations, and improving sexual performance can help reverse this trend. Erectile dysfunction and pulmonary hypertension are usually treated with phosphodiesterase-5 inhibitory agents such as vardenafil, sildenafil, avanafil and tadalafil. Increased levels of cyclic guanosine monophosphate (GMP) enhance vascular smooth muscle relaxation and vasodilation, enhancing penile blood flow and ventilation-perfusion correspondence through PDE5 inhibition. Randomized clinical trials provide critical data on the therapeutic efficacy, safety, and side effects of drugs. However, short-term use does not allow long-term effects to be investigated.
Further research is needed to improve understanding of the effects of PDE-5 inhibition on fertility and well-being, as PDE-5 inhibitors are available over-the-counter in countries such as the United Kingdom (UK). Mendelian randomization is an alternative epidemiologic strategy to improve causal inference in observational research designs that allows genetic variants that predict a particular trait to be randomly assigned at conception.
About the study
In the present study, researchers evaluated the effects of phosphodiesterase-5 on fertility, subjective well-being and sexual behavior in men.
The study analyzed summary data on genomic associations among European men from the International Blood Pressure Consortium (n=757,601) and the UK Biobank (n=211,840) datasets. The study intervention was genetically discounted phosphodiesterase-5 inhibition. Outcome measures were number of sexual partners, number of children born, probability of never having had sex, and subjective well-being.
The researchers performed cis-mendelian randomization to assess the effects of genome-wide phosphodiesterase-5 inhibition on fertility, sexual behavior, and subjective well-being. The team analyzed mostly men, with secondary studies conducted in women to investigate whether the established relationships were associated with the presence of a penis (phosphodiesterase-5 inhibition can help with penile erection).
The team derived estimates of the relationship between blood pressure and variations from genome-wide association analyzes associated with diastolic blood pressure. Genome-wide association studies (GWAS) of diastolic blood pressure included 757,601 European participants of both sexes from 77 cohorts in the UK Biobank and the International Blood Pressure Consortium. The researchers adjusted the groups for age, body mass index (BMI) and sex, and corrected the UK Biobank sample for drug use. The same study provided genome-wide association estimates for diastolic blood pressure to perform a sensitivity analysis. The Elsworth United Kingdom Biobank Genome Association Survey (n=209,872) provided variation data on the number of offspring born.
Results
The researchers identified five genetic variants that could suppress phosphodiesterase-5. The basic version calculated a value of 0.2 mmHg lower diastolic blood pressure and obtained an F statistic of 26, indicating a minimal possibility of instrument bias. Positive control studies revealed a Mendelian randomization association between genomic phosphodiesterase-5 inhibition and pulmonary hypertension and erectile dysfunction.
Genetically discounted phosphodiesterase-5 inhibition was associated with males having 0.3 more children (adjusted false discovery rate) when modeled on the estimated diastolic blood pressure-lowering effect of 100.0 mg sildenafil (5.50 mm Hg) . The relationship, however, was not detected in women. In the localization analysis, the second research hypothesis, that is, a causal genetic variant for the first trait but not for the second trait, showed a probability of 91%, indicating that the statistical power of the findings was insufficient to determine whether the observed association was due to the presence of common causative variants or variants in linkage disequilibrium (LD, i.e. horizontal pleiotropy).
The researchers found no association between genomic phosphodiesterase-5 inhibition and male sexual partners, likelihood of intercourse, or self-reported well-being. The findings of sensitivity studies using systolic blood pressure and Mendelian randomization estimates were comparable.
The study also found no association between genetically estimated phosphodiesterase inhibition and the number of male offspring, except for a weaker association with diastolic blood pressure. After controlling for any pleiotropic bias with cis-mendelian randomization, the main study findings remained similar, indicating that genetic variants may not explain clinically relevant variation in health-related outcomes.
conclusion
Further research is needed to validate this and to avoid encouraging the use of PDE5 inhibitors, which may have adverse effects such as vision loss. Improper use can also lead to hypotension and improperly timed erection. PDE5 inhibitors may increase fertility in male patients with erectile dysfunction.
