All Top PDE-5 Inhibitors Explored and Resources

Icariin is a compound isolated from the plant "Epimedium" also known more commonly as "Horny Goat Weed" - it has been shown to have neuroprotective effects, anti-depressant effects and erectogenic effects. It may help treat Alzheimer's and other memory disorders and can effectively treat high blood pressure.

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MECHANISM #1


PDE-5 Inhibition / cGMP Synthesis / nNOS Acitvator




OVERVIEW / SUMMARY


Icariin decreases the "expression" of PDE-5 enzymes over time, this means that there is a long-term decrease yielding permanent changes in genetic coding to this enzyme. As opposed to just temporarily blocking it, which it also does.


NOTE :: By this mechanism one could presume (though it has lower affinity than Say, Viagra) that it may give one more leverage over time as well as a permanent enhancing effect. Many people ask then, how long before Icariin supplements kick in or how long do they take to work?


ANSWER :: Based on the studies, it would seem plausible that minor effects would be felt in the first couple days (due to inhibition of PDE-5), but the peak effects would come after any where from 2-4 weeks of use(due to downregulation).

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J Sex Med. 2006 Jul;3(4):716-22.
Testosterone:estradiol ratio changes associated with long-term tadalafil administration: a pilot study.
Greco EA1, Pili M, Bruzziches R, Corona G, Spera G, Aversa A.
Author information
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/m2) 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.

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Exposure to phosphodiesterase type 5 inhibitors stimulates aromatase expression in human adipocytes in vitro.
Aversa A1, Caprio M, Antelmi A, Armani A, Brama M, Greco EA, Francomano D, Calanchini M, Spera G, Di Luigi L, Rosano GM, Lenzi A, Migliaccio S, Fabbri A.
Author information
Abstract
INTRODUCTION:
Prolonged tadalafil administration in men with erectile dysfunction is associated with increased testosterone (T): estradiol (E(2)) ratio mainly related to reduction of E(2) levels.
AIM:
To investigate the presence of phosphodiesterase type 5 (PDE5) isoenzyme in primary human visceral adipocytes and whether different PDE5 inhibitors (PDE5i) could directly modulate aromatase (ARO) expression in differentiated human visceral adipocytes in culture.
MAIN OUTCOME MEASURES:
PDE5 mRNA and protein expression in primary human visceral adipocytes as well as mRNA and protein expression of ARO, with functional activity after selective PDE5 blockade by tadalafil and sildenafil.
METHODS:
Purified primary human visceral pre-adipocytes were differentiated ex vivo and were exposed to tadalafil or sildenafil (1 µM) for different intervals of time (6-12-24-96 hours). ARO mRNA content and expression were measured by Western Blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. T and E(2) in supernatants were measured by ELISA also in the presence of letrozole.
RESULTS:
Differentiated adipocytes were found to express detectable levels of PDE5 transcripts. Acute exposure (6 hours) to both PDE5i tadalafil and sildenafil increased ARO mRNA expression by 4.7- and 2.8-fold, respectively (P < 0.001). ARO mRNA and protein levels were increased by the treatment with PDE5i in a time- and dose-dependent manner. Such effect was mimicked by 8-bromo-cGMP but was lost after 24 and 96 hours; differently, the PDE3B specific inhibitor milrinone (1 µM), displayed no effect. Accordingly, long-term exposure (24 and 96 hours) to PDE5i caused a significant increase in E(2) concentrations in the supernatant (1.7 and 2 fold, respectively; P < 0.001), with a parallel reduction of T (15% and 30%, respectively; P < 0.001). Such effect was reversed by the co-incubation with the specific ARO-inhibitor letrozole.
CONCLUSIONS:
Our results demonstrate that PDE5 is expressed in human visceral adipocytes and that acute exposure to PDE5i selectively stimulates ARO expression, which is related to a specific PDE5 blockade. We speculate that modulation of ARO activity by PDE5i could be one of the mechanisms responsible, at least in part, for the beneficial effects of PDE5i on endothelial and metabolic functions.

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J Neurochem. 1996 Nov;67(5):2087-95.
Neurotransmitter-mediated regulation of brain aromatase: protein kinase C- and G-dependent induction.

Abe-Dohmae S1, Takagi Y, Harada N.
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Abstract

Aromatase in the diencephalic neurons, the level of which increases transiently during the prenatal to neonatal period, has been suggested to be involved in control of sexual behavior and differentiation of the CNS. Effects of neurotransmitters on levels of aromatase mRNA in cultured neurons were investigated to determine factors regulating the developmental increase that occurs in level of fetal brain aromatase. The expression of aromatase in diencephalic neurons of fetal mice at embryonic day 13, cultured in vitro, was significantly affected by alpha 1-adrenergic receptor ligands. Aromatase mRNA levels were higher in neurons treated with the alpha 1-agonist phenylephrine than in control neurons, whereas prazosin, an alpha 1-antagonist, suppressed this increase, and ligands for alpha 2- or beta-adrenergic receptors did not exert any influence. The profile of alpha 1-adrenergic receptor subtypes during actual development in vivo suggested that the alpha 1B subtype is in fact responsible for the signal transduction. Substance P, cholecystokinin, neurotensin, and brain natriuretic peptide also increased the level of expression along with phorbol 12-myristate 13-acetate and dibutyrylcyclic GMP, whereas forskolin and dibutyryl-cyclic AMP caused a decrease. These data indicate that stimulation via alpha 1 (possibly alpha 1B)-adrenergic receptors, as well as receptors of specific neuropeptides, controls the expression of aromatase in embryonic day 13 diencephalic neurons through activation of protein kinase C or G. beta-Adrenergic receptors would not appear to participate in the regulation, judging from their developmental profile, although cyclic AMP might be a suppressive second messenger.

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Int J Fertil Menopausal Stud. 1993 Jan-Feb;38(1):50-6.
Gonadotropin-releasing hormone has a biphasic action on aromatase activity through protein kinase C in granulosa cells.

Imai A1, Iida K, Tamaya T.
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Abstract

Gonadotropin-releasing hormone (GnRH) exerts direct effects on the ovary by binding to its specific receptor, and stimulates inositol phospholipid turnover in granulosa cells. This study was undertaken to determine the involvement of protein kinase C in the action of GnRH on follicle-stimulating hormone (FSH)-stimulated aromatase activity in rat granulosa cells. The aromatase activity was examined by conversion of exogenously supplied androstenedione to estrogen. FSH stimulated aromatase activity, with a low rate of estrogen production for the first 18 hours, followed by a high rate of production on further incubation. Addition of GnRH potentiated the aromatase response to FSH in the first 18 hours, but caused a dose-dependent inhibition of the FSH-stimulated aromatase activity from 20 to 45 hours of incubation. Half-maximal effects of GnRH occurred at 10 nM. Both of the biphasic actions of GnRH on aromatase response to FSH were mimicked by protein kinase C activators, phobol myristate acetate (PMA) and oleoylacetyl glycerol; maximal effects occurred at 1 to 10 ng/mL. When the cells were exposed first to FSH for 18 hours and then to PMA, the second phase of estrogen production was also suppressed. The second phase, producing quantitative estrogen, might result from induction of the enzyme, because cycloheximide (100 ng/mL) prevented the FSH-induced activation of aromatase from 20 hours of incubation. These results indicate that the biphasic actions of GnRH on FSH-stimulated aromatase activity are mediated by protein kinase C. The inhibitory action of GnRH on quantitative steroidogenesis caused by prolonged FSH stimulation might be expressed through the impaired induction of aromatase.

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