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.
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. Psychological state, such as emotional tiredness, anxiety or stress, can impact sexual performance.
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.
|Factors||Implications in the erection mechanism|
|Age||+ 60 years old||Vascular health decrease /Blood flow decrease|
|Psychological State||Emotional tiredness, Anxiety, Stress||Loss of libido, Overinhibition|
|Organic Factors||Inadequate nitric oxide release||Lack of NO bioavailability /Blood flow decrease|
|Impaired smooth muscle||Lack of relaxation/ Blood flow decrease|
|Damage to the nerves||Neurochemical message transmission interrupted|
|Impaired blood pressure||Blood flow decrease|
|Alcohol||Slowing of nerve communication|
|Tobacco||Blood flow decrease|
NO is likely the main mediator involved in penile erection mechanism and the most important target to improve organic factors implicated in erectile function.
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)
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 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 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.
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 in Iran for its effects on sexual and libido applications, was combined in Nexira's formulation, to achieve synergistic activities.
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).
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 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 dysfunction. J Andra/. May-Jun, 2006, 27(3):335-47. READ STUDY
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. READ STUDY
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. READ STUDY
Burnett, Arthur L. 2006. The role of nitric oxide in erectile dysfunction: implications for medical therapy. Clin Hypertens (Greenw ich). Dec, 2006, (12 Suppl 4):53-62. READ STUDY
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. READ STUDY
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 Study. Arch Ital Ural Andra/. Dec, 2013, 85(4):184-9. READ STUDY
Chughtai B, Lee RK, Te AE, Kaplan SA. 2011. Metabolic syndrome and sexual dysfunction. Curr Opin Ural. Nov, 2011, 21(6) :514-8. READ STUDY
Costa, Pierre. 2008. Benign Prostatic Hyperplasia and Sexual Dysfunction. Abstracts of the 9th Congress of the European Federation of Sexology. April, 2008, Volume 17, Supplement 1, Pages S12. READ STUDY
Dean RC, Lue TF. 2005. Physiology of penile erection and pathophysiology of erectile dysfunction. Ural Clin North Am. Nov, 2005, 32(4):379-95. READ STUDY
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. READ STUDY
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. READ STUDY
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 dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Ural. Oct, 2011, 60(4):809-25. READ STUDY
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. READ STUDY
Glina S, Glina FP. 2013. Pathogenic mechanisms linking benign prostatic hyperplasia, lower urinary tract symptoms and erectile dysfunction. Ther Adv Ural. Aug, 2013 , 5(4):211-8. READ STUDY
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. READ STUDY
http://www.diabetesindia.com/. Physiology of Penile Erection. Diabetes India. [Online] [Cited : August 21, 2015 .] http://w ww .diabete sindia .com/. READ STUDY
Impotence. NIH Consensus Development Panel on ED. 1993. 1993 . JAMA 270:83- 90. READ STUDY
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. READ STUDY
Klotz T, Mathers MJ, Braun M, Bloch W, Engelmann U. 1999. Effectiveness of oral L-arginine in first line treatment of erectile dysfunction in a controlled crossover study. Ural Int. 1999, 63(4):220-3. READ STUDY
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. READ STUDY
Laumann EO, Paik A, Rosen RC. 1999. The epidemiology of erectile dysfunction: results from the National Health and Social Life Survey. Int J lmpot Res. Sep, 1999, Suppl 1:S60-4. READ STUDY
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. READ STUDY
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 dysfunction 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. READ STUDY
Lue, Tom F. 2000. Erectile dysfunction. 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. READ STUDY
Meller SM, Stilp E, Walker CN, Mena-Hurtado C. 2015. The link between vasculogenic erectile dysfunction, coronary artery disease, and peripheral artery disease : role of metabolic factors and endovascular therapy. J Invasive Cardiol. Jun, 2015, 25(6):313-9. READ STUDY
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. READ STUDY
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 dysfunction and coronary artery disease. Am J Cardiol. Dec, 2005, 96(12B):19-23. READ STUDY
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 dysfunction. Naunyn Schmiedebergs Arch Pharmacol. Sep, 2013, 386(9) :805-11.
Nicolosi A, Glasser DB, Moreira ED, Villa M. 2013. Prevalence of erectile dysfunction and associated factors among men without concomitant diseases: a population study. Int J lmpot Res. Aug, 2013, 15(4):253-7. READ STUDY
Nunes KP, Labazi H, Webb RC. 2012. New insights into hypertension-associated erectile dysfunction. Curr Opin Nephrol Hypertens . March 2012, 21(2):163-70. READ STUDY
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 dysfunction in rats. Int J lmpot Res. Feb, 2003, 15 (1):26-37 . READ STUDY
Selvin E, Burnett AL, Platz EA. 2007. Prevalence and risk factors for erectile dysfunction in the US. Am J Med. Feb, 2007, 120(2) :151 -7. READ STUDY
Shamsa A, Hosseinzadeh H, Molaei M, Shakeri MT, Rajabi 0. 2009. Evaluation of Crocus sativus L. (saffron) on male erectile dysfunction: a pilot study. Phytomedicine. Aug, 2009, 16(8):690-3. READ STUDY
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 dysfunction in middle-aged rats: prevention by antioxidant therapy. J Sex M ed. Apr, 2013, 10(4):960- 71. READ STUDY
Soni SD, Song W, West JL, Khera M. 2013. Nitric oxide-releasing polymeric microspheres improve diabetes-related erectile dysfunction. J Sex Med. Aug, 2013, 10(8) :1915-25. READ STUDY
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. READ STUDY
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. READ STUDY
Zernecke A, Weber C. 2010. Chemokines in the vascular inflammatory response of atherosclerosis. Cardiovasc Res. May, 2010, 86(2):192-201. READ STUDY