Increased libido from Dutasteride but decreased from Finasteride? What’s going on?

The explanation we commonly hear about changes in libido from 5 alpha reductase inhibitors, is in regards to their alteration of estradiol levels. However today I would like to go beyond that explanation to explain why people often experience increased libido from Dutasteride but not Finasteride, and why some selective people experience significant libido side effects from Finasteride but why we don’t hear the same about Dutasteride. After All I’ve never heard anyone say Post-Dutasteride Syndrome. A 2019 Meta-analysis titled ‘Adverse Sexual Effects of Treatment with Finasteride or Dutasteride for Male Androgenetic Alopecia: A Systematic Review and Meta-analysis’ confirmed what we had suspected based on the decades of anecdotes, Dutasteride despite being a more potent 5 alpha reductase inhibitor is actually associated with less side effects.

Finasteride and Dutasteride are 5 alpha reductase inhibitors, inhibiting the conversion of Testosterone into DHT within the body. When there is an increase in Testosterone after taking 5 alpha reductase inhibitors, more Testosterone can be converted into estrogen via the Aromatase enzyme. Depending on the availability of the Aromatase enzyme, users may experience an excess (above the reference range) or deficiency in Estrogen, thus causing sexual side effects in men, as both low and high Estrogen are both responsible for decreased libido in men. However on the flip side, if Estrogen is in normal ranges prior to starting 5 Alpha Reductase inhibitors some men often report an increase in libido. However Finasteride use is more often associated with sexual side effects and decreased libido, despite it being a less potent 5 alpha reductase inhibitor compared to Dutasteride.

So what the hell is going on here?

Why is Dutasteride not associated with persistent sexual side effects are cessation? And why are there studies that show the rate of sexual side effects are lower in Dutasteride users.

Well the reason might surprise you.

Critical to sexual desire, libido, and erection quality in men is androgens binding to androgen receptors in the brain and in the penis. Anything that significantly blocks this from happening will interfere with libido. So anything that lowers androgen levels in these areas, anything that lowers androgen receptor levels in these areas, and anything that blocks the androgens from binding to the androgen receptors will decrease libido and erection quality. 

Now recently, I discovered this paper titled ‘The antiandrogenic effect of finasteride against a mutant androgen receptor’, which speculated that Finasteride may act as an direct antagonist of the androgen receptor, meaning it binds to androgen receptors blocking androgens from binding to androgen receptors and exerting their positive effects in regards to sexual function.

Finasteride might bind to the androgen receptor (AR) due to its structural similarity to dihydrotestosterone (DHT).

It reviewed two papers in this regard both titled ‘Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line’ and ‘Antiandrogenic effects of novel androgen synthesis inhibitors on hormone-dependent prostate cancer’. The fact that these findings were all based on LNCaP cells, which carry a T877A mutation in the ligand binding domain of AR, prompted further investigation into whether the antagonistic effect of finasteride might be observed similarly with the wild-type AR, which the first paper investigated.

In contrast there is no evidence that Dutasteride is an antagonist of the androgen receptor.  

A great review paper titled ‘Recent Advances in Drug Design and Drug Discovery for Androgen-Dependent Diseases’ reviewed Dutasteride in great detail and concluded it does not bind to the androgen receptor.

Therefore there is novel evidence that the decrease in libido from Finasteride is partly attributed to its androgen receptor antagonism, and explains why less people experience decreased libido on Dutasteride than Finasteride, as Dutasteride doesn’t have an affinity for the androgen receptor.

References:

Lazier CB, Thomas LN, Douglas RC, Vessey JP, Rittmaster RS. Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line. Prostate. 2004 Feb 1;58(2):130-44. doi: 10.1002/pros.10340. PMID: 14716738.

Long BJ, Grigoryev DN, Nnane IP, Liu Y, Ling YZ, Brodie AM. Antiandrogenic effects of novel androgen synthesis inhibitors on hormone-dependent prostate cancer. Cancer Res. 2000 Dec 1;60(23):6630-40. PMID: 11118046.

Lee, S., Lee, Y. B., Choe, S. J., & Lee, W.-S. (2018). Adverse Sexual Effects of Treatment with Finasteride or Dutasteride for Male Androgenetic Alopecia: A Systematic Review and Meta-analysis. Acta Dermato-Venereologica, 99(1), 12–17. https://doi.org/10.2340/00015555-3035

Cabeza M, Sánchez-Márquez A, Garrido M, Silva A, Bratoeff E. Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases. Curr Med Chem. 2016;23(8):792-815. doi: 10.2174/0929867323666160210125642. PMID: 26861003; PMCID: PMC5412001.