Association of genetically proxied PDE5 inhibition with measures of fertility, sexual behavior, and wellbeing

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Dec 14 2023

In a recent study published in BMJ, researchers performed a two-sample Mendelian randomization analysis to investigate the associations between genetically proxied (via a surrogate biomarker) suppression of phosphodiesterase 5 (PDE5), a recognized pharmacological target for erectile dysfunction, fertility, subjective wellness, and sexual behavior.

Background

Fertility is decreasing in many nations, and improving sexual performance might help reverse this trend. Erectile dysfunction and pulmonary hypertension are typically treated with phosphodiesterase-5 inhibitory agents such as vardenafil, sildenafil, avanafil, and tadalafil. Elevated cyclic guanosine monophosphate (GMP) levels enhance the relaxation of vascular smooth muscles and vasodilation, enhancing the flow of blood to the penile organ and ventilation-perfusion match via inhibiting PDE5. Randomized clinical trials provide critical data on therapeutic effectiveness, safety, and side effects of drugs. However, short-term usage does not allow for investigating long-term outcomes.

Further investigation is required to improve understanding of the effects of PDE-5 inhibition on fertility and wellness, as PDE-5 inhibitory agents are available without a prescription in nations like the United Kingdom (UK). Mendelian randomization is an alternate epidemiological strategy for improving causal inferences in observational research designs that allows for the random assignment of genetic variations predicting a specific trait at conception.

About the study

In the present study, researchers evaluated phosphodiesterase-5 effects on fertility, subjective wellness, and sexual behavior of males.

The study analyzed summary data on genomic associations among European males from the International Consortium for Blood Pressure (n=757,601) and the UK Biobank (n=211,840) datasets. The study intervention was genetically proxied phosphodiesterase-5 inhibition. The outcome measures were the number of sexual partners, the number of children fathered, the likelihood of never having had sex, and subjective wellness.

The researchers performed cis-mendelian randomization to evaluate the effects of genomically proxied phosphodiesterase-5 inhibition on fertility, sexual behavior, and subjective wellness. The team primarily analyzed men, with secondary studies conducted in women to investigate whether the determined relationships were associated with penile presence (phosphodiesterase-5 inhibition may aid penile erection).

The team derived estimates of the link between blood pressure and variations from diastolic-type blood pressure-related genomic association analyses. Genome-wide association studies (GWAS) on diastolic-type blood pressure included 757,601 European participants of both sexes from 77 groups in the United Kingdom Biobank and the International Consortium for Blood Pressure. The researchers adjusted the groups for age, body mass index (BMI), and gender and corrected the United Kingdom Biobank sample for drug usage. The same study provided genomic association estimations for diastolic-type blood pressure to perform sensitivity analysis. The Elsworth United Kingdom Biobank genome-wide association research (n=209,872) yielded variant-outcome data on the number of offspring fathered.

Results

The researchers identified five genetic variations that could suppress phosphodiesterase-5. The lead version estimated a 0.2 mm of mercury lower diastolic-type blood pressure value, and an F statistic value of 26 was obtained, indicating a minimal instrumental bias probability. Positive control studies revealed a Mendelian randomization association between genomically proxied phosphodiesterase-5 inhibition and pulmonary hypertension and erectile dysfunction.

Genetically proxied phosphodiesterase-5 inhibition was related to males having 0.3 more children (false discovery rate adjusted) when mounted to the estimated diastolic-type blood pressure-reducing impact of 100.0 mg sildenafil (5.50 mm of Hg). The relationship, however, was not detected in women. In colocalization analysis, the second research hypothesis, i.e., a causal genetic variant for the first trait but not the second trait, showed a likelihood of 91%, indicating that the statistical power of the findings was inadequate to determine whether the association observed was due to the presence of shared causal variants or variants in linkage disequilibrium (LD, i.e., horizontal pleiotropy).

The researchers found no link between genomically proxied phosphodiesterase-5 inhibition and male sexual partners, sexual intercourse likelihood, or self-documented wellness. The findings of sensitivity studies utilizing systolic-type blood pressure and Mendelian randomization estimates were comparable.

The study also discovered no link between genetically estimated phosphodiesterase inhibition and the number of offspring of men, except for the weakest link with diastolic-type blood pressure. After controlling for any pleiotropic bias with cis-mendelian randomization, the primary study’s findings remained similar, indicating that genetic variations may not explain clinically significant variance in health-associated outcomes.

Conclusion

Further research is required to validate this and prevent encouraging the use of PDE5 inhibitors, which can have adverse effects such as eyesight loss. Incorrect usage can also result in hypotension and improperly timed erections. PDE5 inhibitors may increase fertility in male erectile dysfunction patients.