repair nitric oxide (NO) producing cells + increased NO  + 50% increase in blood flow + increased libido  +  sustained performance




A Significant Health Issue for Men


Sexual activity is an important indicator of the overall health and well-being of men. A healthy and satisfying sex life is closely associated with a healthy lifestyle. Male sexual performance is mainly evaluated by erectile function.


Sexual function is physiologically correlated with age and also with one’s psychological and emotional state.  Approximately  50% of men between 40 and 75 years old could be concerned by a decrease of erectile function (NIH Consensus Conference, 2012, 2013).


A decrease of sexual performance could lead to important psychological consequences such as: anxiety, mood and lack of self-esteem, contributing to a vicious circle.


Sexual performance factors


Men’s sexual function is based on erection ability to be spontaneous, firm and lasting all intercourse.


The erection mechanism is the combination of three functions.  First, the brain is involved by controlling all  male senses (sight, hearing, smell touch and thought).


Then, physical or psychogenic stimulation induces a neurochemical message, carried by the nerves to the penis artery.


Nitric oxide (NO) production is then stimulated in endothelial cells which leads to blood flow increase within the penis artery.  At this stage, the smooth muscle is relaxed, the sinusoid cavities are swelled with blood and the vein is flattened which limits the blood exit. The maximum erection rigidity is now achieved.


The sexual function of healthy men, or the erection ability, closely depends on two factors. (1). Psychological state, such as emotional tiredness, anxiety or stress, can impact sexual performance.


(2). Organic factors such as NO bioavailability or smooth muscle cell relaxation have effects on blood flow. A healthy blood flow promotes erectile function.


About 80% of men with a decrease of sexual performance report an organic cause, especially  vasculogenic (circulation) factor, age-related NO deprivation/reduced blood flow, even if psychogenic factors (depression, anxiety…) are often present.


Decrease of blood flow has been associated with low erectile function. A decrease of erectile function is considered as the early stage of vascular decline associated with age. Therefore, maintenance of healthy blood flow represents a long term interesting challenge to preserve erectile function and sexual performance.

Table 1: Causes having effect on erection mechanism

NO is likely the main mediator involved in penile erection mechanism and the most important
target to improve organic factors implicated in erectile function

Erection Mechanism at

the Macroscopic Level

Penile erection (PE) is the result of a complex physiologic process involving a coordinated interaction between the blood vessels, the nerves and specific hormones.



In the flaccid state, arterial vessels contained in the corpus cavernosum are constricted when cavernosal smooth muscles are contracted, allowing only a weak blood flow (Fig. 1).


Sexual stimulation, either psychogenic or reflexogenic, triggers neuronal NO release which initiates penile       tumescence (normal engorgement with blood of the erectile tissues) and neuronal acetylcholine (Ach) release which eases tumescence promotion (Burnett, 2004).


ACh activates endothelial nitric oxide synthase (eNOS)  transforming arginine precursor into endothelial nitric oxide (eNO).  After several biochemical reactions (Fig. 2), the relaxation of cavernosal smooth muscles leads to an increase of blood flow in the corpus cavernosum.  (Burnett, 1997)

Figure 1 Erection mechanism of penile erection

Mechanism of Action

NO dependent blood flow: the most targeted mechanism of action


Decrease of sexual performance is mainly described as coming from a lack of NO bioavailability (Burnett, 2006;  Burnett,  1997).  Different  approaches exist but the great majority are using the NO dependent blood flow modulation pathway.


Most of the products supporting erectile function and male sexual performance are targeting NO dependent blood flow mechanism by modulating biochemicals implicated at different steps (Muniz JJ, 2013).


A part of these approaches are focusing on direct NO replenishment in the corpus cavernosum (Soni SD, 2013) or on endothelial NO synthase activation (Subramoniam  A,  2013): this is the mechanism of action of OxyStim.

In addition to its important role on smooth muscles relaxation previously described, eNO source from corpus cavernosum cells enhances the Vascular Endothelial Growth Factor (VEGF) synthesis (Komori 2008).  VEGF  is recognized to participate to the erectile function improvement by inhibiting endothelial apoptosis (processes leading to the death of cells (Rogers RS, 2003; Liu G, 2013).


Furthermore, administration of pure exogenous (taken orally) arginine, the eNOS substrate, did not demonstrate significant efficiency to improve erectile function (Klotz T, 1999), meaning that targeting NO precursor is not adapted.  It should be more relevant to act on the enzyme in charge of eNO synthesis (eNOS) to obtain higher quantity of bioavailable NO. That's what OxyStim's active eNoSTIM achieves and why arginine-based NO enhancers have poor efficacy.


NO synthase enzyme, and especially eNOS from endothelial cells in the corpus carvernosum, is a  remarkable  target with a high potential regarding male sexual performance. Studies indicate that OxyStim's EnoSTIM lives up to that potential by increasing blood flow by up to 50% to penile erectile tissue.

OxyStim's EnoSTIM activated eNOS by 43%, inducing a 24% increase of bioavailable NO.
This activity resulted in a 50% increase in vasodilation or blood flow to the bodys'
cells, tissues, and organs including
penile erectile tissue.

OxyStim: Formulation of proprietary grape and apple skin polyphenols and saffron

To obtain an optimized action on NO secretion, OxyStim's research licensor, Nexira, developed a specific     combination of flavonoids extracted proprietarily from grape skin and polyphenols from apple skin.  Saffron, traditionally used historically for its effects on sexual and libido applications, was combined in Nexira's formulation, to achieve synergistic activities.


In vitro - HUVEC cells trials:

Nexira's research demonstrated that eNOS activation is permitted through phosphorylation of serine 1117 (mechanism of regulating protein function and transmitting signals throughout cells).  Among several formulations, Nexira's proprietary acute polyphenol formulation, was selected as it reached its highest results on serine 1177 phosphorylation during an in vitro trial on endothelial cells (HUVEC).


EnoSTIM showed the highest potential on eNOS activation

The combination of the proprietary acute polyphenols and saffron showed an activity on eNOS with complementary mechanisms, supporting their unique synergy: acute polyphenols act on enzyme activation (through Serine 1177 phosphorylation) while saffron increases mRNA expression (messenger RNA molecules convey genetic information from DNA to the ribosome, where they specify the amino acid sequence of the protein products of gene expression) leading to an augmentation of this enzyme amount (Fig. 3).

Figure 2: Molecular mechanism of penile smooth  muscle relaxation in corpus cavernosum

Figure 3: Synergistic effects of ingredients composing EnoSTIM (acute polyphenols and saffron)



Agarwal A,  Nandipati KC,  Sharma RK,  Zippe CD,  Raina R.  2006.  Role of oxidative stress in the pathophysiological mechanism of erectile insufficiency. J Andra/. May-Jun, 2006, 27(3):335-47.


AI-Rehaily AJ, Alhowiriny TA, El-Tahir KE, AI-Taweel AM, Perveen S. 2015. Molecular mechanisms that underlie the sexual  stimulant actions of Avicennia marina (Forssk.) Vierh. and Crocus sativus L. Pak J Pharm Sci. Jan, 2015, 28(1):49-58.


Broekhuizen LN, van Wijk DF, Vink H, Stalmach A, Crozier A, Hutten BA, Kastelein JJ, Hugenholtz PG,  Koenig  W,  Stroes  ES.  2011.  Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a  polyphenol-rich extract in subjects with clustered cardiometabolic risk factors. Br J Nutr. Nov, 2011, 106(9) :1416- 22.


Burnett, Arthur L. 2006. The role of nitric oxide in erectile dysfunnction: implications for medical therapy . Clin Hypertens (Greenw ich). Dec, 2006, (12 Suppl 4):53-62.


Burnett, Arthur L. 1997. Nitric oxide in the penis: physiology and pathology. J Ural. 1997, 157(1):320-4 .

    __ 2004. Novel nitric oxide signaling mechanisms regulate the erectile response . Int J lmpot Res. Jun, 2004, Suppl 1:S15-9.


Cai T, Morgia G, Carrieri G, Terrone C, Imbimbo C, Verze P, Mirone V. 2013. An improvement in sexual function is  related to better quality of  life,  regardless of  urinary function improvement: results from the IDIProst®  Gold Stud y.

Arch Ital Ural Andra/.  Dec, 2013, 85(4):184-9.


Chughtai B, Lee RK, Te AE, Kaplan SA. 2011. Metabolic syndrome and sexual insufficiency .  Curr  Opin Ural. Nov, 2011, 21(6) :514-8.


Costa, Pierre. 2008. Benign Prostatic Hyperplasia and Sexual insufficiency . Abstracts of  the 9th Congress of  the  European Federation of Sexology.  April, 2008, Volume 17, Supplement  1, Pages S12.


Dean RC, Lue TF. 2005. Physiology of penile erection  nd pathophysiology of erectile insufficiency. Ural Clin North Am. Nov, 2005, 32(4):379-95.


Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. 1994. Impotence and its medical and psychosocial  correlates: results of the Massachusetts Male Aging Study. J Ural. Jan,  1994, 151(1):54- 61.


Freedman JE, Parker C 3rd, Li L, Perlman JA, Frei B, Ivanov V, Deak LR, lafrati MD, Folts JD. 2001. Select flavonoids  and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation. Jun, 2001, 103(23):2792-8.


Gacci M,  Eardley I, Giuliano F, Hatzichristou D, Kaplan SA, Maggi M,  McVary KT, Mirone V, Porst H, Roehrborn CG. 2011. Critical analysis of the relationship between sexual insufficiencys and lower urinary tract symptoms due to benign prostatic hyperplasia.  Eur Ural. Oct, 2011, 60(4):809-25.


Giles,  Thomas  D.  2006.  Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. J Clin Hypertens (Greenwich).  Dec, 2006, 8(12 Suppl 4):2-16.


Glina S, Glina FP. 2013. Pathogenic mechanisms linking benign prostatic hyperplasia, lower urinary tract symptoms and erectile insufficiency . Ther Adv Ural. Aug, 2013 , 5(4):211-8.


Hosseinzadeh  H, Ziaee T, Sadeghi  A. 2008. The effect of saffron, Crocus sativus stigma, extract and its constituents, safranal and crocin on sexual behaviors in normal male rats . Phytomedicine. Jun, 2008, 15(6- 7):491-5. Physiology of Penile  Erection. Diabetes India.  [Online]  [Cited :  August 21, 2015 .]
http://w ww .diabete sindia  .com/.


Impotence. NIH Consensus Development Panel on ED. 1993. 1993 . JAMA 270:83- 90.


lsidori AM,  Buvat J,  Corona G, Goldstein I, Jannini EA, Lenzi A, Porst H, Salonia A, Traish AM, Maggi M. 2014. A critical analysis of  the role of testosterone in erectile function: from pathophysiology to treatment-a  systematic  review . Eur Ural. Jan, 2014, 65(1):99-112.


Klotz T, Mathers MJ, Braun M,  Bloch W,  Engelmann U. 1999. Effectiveness of oral L-arginine in first­ line treatment of erectile insufficiency in a controlled crossover study  . Ural Int. 1999, 63(4):220-3.


Komori K, Tsujimura  A, Takao T, Matsuoka Y, Miyagawa  Y, Takada  S, Nonomura  N, Okuyama  A. 2008. Nitric oxide synthesis leads to vascular endothelial growth factor synthesis via the NO/cyclic guanosine 3',5'-monophosphate (cGMP)  pathway in human corpus cavernosal smooth muscle cells. J Sex  Med.  Jul, 2008, 5(7):1623-35 .


Laumann EO, Paik A, Rosen RC. 1999. The epidemiology of erectile insufficiency: results from the National Health and Social Life Survey. Int J lmpot Res. Sep, 1999, Suppl 1:S60-4 .


Lautenschlager M,  Sendker J, Huwel S, Galla HJ, Brandt S, Dufer M, Riehemann K, Hensel A. 2015. Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier. Phytomedicine. Jan, 2015, 22(1):36-44.


Liu G, Sun X, Bian J, Wu R, Guan X, Ouyang B, Huang Y, Xiao H, Luo D, Atala A, Zhang Y, Deng C. 2013. Correction of diabetic erectile insufficiency with adipose derived stem cells modified with the vascular endothelial growth factor gene in a rodent diabetic model. PLoS One. Aug, 2013, 30;8(8):e72790.


Lue, Tom F. 2000. Erectile insufficiency.  N Eng/J Med. Jun, 2000, 342(24): 1802-13.


Mancini A, Serrano-Diaz J, Nava E, D'Alessandro AM,  Alonso  GL, Carmona  M,  Llorens  S.  2014. Crocetin,  a  carotenoid derived from saffron (Crocus  sativus  L.), improves acetylcholine-induced vascular relaxation in hypertension . J Vase Res. 2014, 51(5):393-404.


Meller SM,  Stilp E,  Walker CN,  Mena-Hurtado C. 2015. The link between vasculogenic erectile insufficiency, coronary   artery disease, and peripheral artery disease : role of metabolic factors and endovascular therapy . J Invasive Cardiol. Jun, 2015, 25(6):313-9.


Modabbernia  A, Sohrabi  H, Nasehi  AA, Raisi F, Saroukhani  S, Jamshidi  A, Tabrizi  M,  Ashrafi  M, Akhondzadeh  S. 2012. Effect  of  saffron  on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology (Berl). Oct, 2012, 223(4):381-8.


Montorsi P, Ravagnani  PM, Galli S, Rotatori F, Briganti  A, Salonia  A, Rigatti P, Montorsi F. 2005. The artery size hypothesis: a macrovascular link between erectile insufficiency and coronary artery disease. Am J Cardiol. Dec, 2005, 96(12B):19-23 .


Muniz JJ, Lacchini R, Sert6rio JT, Jordao AA Jr, Nobre YT, Tucci S Jr, Martins AC, Tanus-Santos JE.

2013. Low nitric oxide bioavailability is associated with better responses to sildenafil in patients with erectile insufficiency . Naunyn Schmiedebergs  Arch Pharmacol. Sep, 2013, 386(9) :805-11.



Nicolosi  A, Glasser  DB,  Moreira  ED, Villa  M. 2013.  Prevalence of erectile insufficiency and associated factors among  men without concomitant diseases: a population study . Int  J  lmpot  Res.  Aug,  2013, 15(4):253-7.


NIH Consensus Conference. Meller et al. 2013, Nunes et al. 2012. 2012, 2013. s.1 .  : www. who .int, 2012, 2013.


Nunes KP, Labazi H, Webb RC. 2012. New insights into hypertension-associated erectile insufficiency. Curr Opin Nephrol Hypertens . March 2012, 21(2):163-70 .


Rogers RS, Graziottin TM, Lin CS, Kan YW, Lue TF. 2003. lntracavernosal vascular endothelial growth factor  (VEGF)  injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile insufficiency in rats. Int  J lmpot Res. Feb, 2003, 15 (1):26-37 .


Selvin E, Burnett AL, Platz EA. 2007. Prevalence and risk factors for erectile insufficiency in the US. Am J

Med. Feb, 2007, 120(2) :151 -7.


Shamsa A, Hosseinzadeh H, Molaei M,  Shakeri MT,  Rajabi 0.  2009. Evaluation of Crocus sativus L. (saffron) on male erectile insufficiency: a pilot study. Phytomedicine. Aug, 2009, 16(8):690-3.


Silva FH, Monica FZ, Bau FR, Brugnerotto AF, Priviero FB, Toque HA, Antunes E. 2013. Superoxide anion production   by NADPH oxidase plays a major role in erectile insufficiency in middle-aged rats: prevention by antioxidant therapy. J Sex M ed. Apr, 2013, 10(4):960- 71.


Soni SD, Song W, West JL, Khera M.  2013. Nitric oxide-releasing polymeric microspheres improve diabetes-related erectile insufficiency. J Sex Med. Aug, 2013, 10(8) :1915-25.


Subramoniam  A, Gangaprasad  A, Sureshkumar  PK, Radhika  J, Arun KB. 2013.  A novel aphrodisiac compound from an orchid that activates nitric oxide synthases. Int J lmpot Res. Nov-Dec, 2013, 25(6):212- 6.


Tang FT, Qian ZY, Liu PQ, Zheng SG, He SY, Bao LP, Huang HQ. 2006. Crocetin improves endothelium­ dependent relaxation of thoracic aorta in hypercholesterolemic rabbit by increasing eNOS activity. Biochem Pharmacol.  Aug, 2006, 72(5):558-65.


WHO. Sexual health issues. World Health Organization . [Online] [Cited: June 10, 2015 .] www. who. int.


Zernecke A, Weber C.  2010.  Chemokines in the vascular inflammatory response of atherosclerosis . Cardiovasc Res. May, 2010, 86(2):192-201.

© Copyright 2020 DEVORE NUTRACEUTICALS, LLC | All Rights Reserved

Privacy Policy | Terms of Service | Secure Shopping with 100% Industry Standard SSL

EnoSTIM™ is a registered trademark of Nexira.

†This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.