Tadalafil (Cialis) Decreases Estradiol.

[Nelson Vergel]

ABSTRACT

Introduction.  It has been reported that lack of sexual activity due to erectile dysfunction (ED) may be associated with testosterone (T) decline.

Aim.  To investigate whether the known changes in sex hormones associated with resumption of sexual activity are sustained in the long term.

Main Outcome Measures.  Primary endpoints were variations from baseline of steroid hormones: total T, free T (f T), and estradiol (E). Secondary endpoints were variations of erectile function domain scores at International Index of Erectile Function-5 (IIEF-5).

Methods.  In an open-label fashion, 20 patients (mean age 54.8 ± 8.4 years) received tadalafil 10–20 mg on demand for 12 months. Exclusion criteria were those reported for phosphodiesterase inhibitors, including hypogonadism and hyperprolactinemia.

Results.  Tadalafil assumption was safe and well tolerated (overall adverse effects in 15% of patients) and none discontinued medication. A significant decrease in E levels occurred at the end of the study (from 19.9 ± 9.6 to 16.6 ± 8.1 ng/dL, P = 0.042 vs. baseline), with parallel increase in the T:E ratio (26.3 ± 15.3 to 32.6 ± 17.7, P = 0.05), whereas no changes in T and f T serum levels were observed, respectively (411.4 ± 131.4 to 434.2 ± 177.1 ng/dL and 47.7 ± 15.3 to 49.9 ± 19.1 pmol/L, not significant). Interestingly, nonparametric subgroup analysis for related samples revealed that E decrease was detectable only in lean (N = 14) but not in obese (N = 6, body mass index > 27.5 kg/m[SUP]2[/SUP]) subjects (17.8 ± 10.1 vs. 13.5 ± 6.8, P < 0.05). A net increase in IIEF-5 scores was observed at the endpoint (13.7 ± 5.9 vs. 25.7 ± 2.9, P < 0.0001).

Conclusions.  Sustained improvement in sexual function after 12 months of tadalafil administration is associated with increased T:E ratio mainly related to reduction of E levels. We hypothesize that androgen–estrogen cross-talk and possible inhibition of aromatase activity during chronic exposure to tadalafil might have a role in the regulation of erectile function.


Greco EA, Pili M, Bruzziches R, Corona G, Spera G, and Aversa A. Testosterone:estradiol ratio changes associated with long-term tadalafil administration: A pilot study. J Sex Med 2006;3:716–722.

 

[Nelson Vergel]

This recent study may explain why tadalafil (Cialis) increases testosterone and decreases estradiol.

It increases androgen receptor protein expression while decreasing estrogen receptor alpha expression.


Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.
Aversa A, et al. J Endocrinol Invest. 2015.

Abstract
PURPOSE: Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD).

METHODS: Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression.

RESULTS: Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ER, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation.

CONCLUSIONS: Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

 

[Jasen Bruce]

Very interesting. I wonder if this effect is limited to just tadalafil or if it occurs with other PDE-5 inhibitors?

 

[Nelson Vergel]

Tadalafil (Cialis) improves lean mass and endothelial function in nonobese men

 

[Weasel]

This recent study may explain why tadalafil (Cialis) increases testosterone and decreases estradiol.

It increases androgen receptor protein expression while decreasing estrogen receptor alpha expression.


Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.
Aversa A, et al. J Endocrinol Invest. 2015.

Abstract
PURPOSE: Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD).

METHODS: Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression.

RESULTS: Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ER&#945;, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation.

CONCLUSIONS: Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

Does this effect continue after discontinuation?

 

[Nelson Vergel]

The study on lean mass said:

" increased abdominal lean mass that returned to baseline after 2 months withdrawal."

No such info on the one referring to estradiol but I would suspect faster return to baseline for estradiol after withdrawal.

 

[Weasel]

The study on lean mass said:

" increased abdominal lean mass (p&#8201;<&#8201;0.01) that returned to baseline after 2 months withdrawal."

No such info on the one referring to estradiol but I would suspect faster return to baseline for estradiol after withdrawal.

Excellent, Thanks Nelson.