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Nitric Oxide's Role in Sexual Hormonal Pathway
Introduction to Nitric Oxide
Nitric oxide has been proven to play a role in male sexual activity, particularly in the pathway for male erection. Numerous studies have examined the role of nitric oxide deficiency in male erectile dysfunction (1). The focus of this analysis however, will be to explain the role nitric oxide can play on hormonal release, both as an activator and an inhibitor.
An overview of the physiological pathway of nitric oxide release will first be provided. Examinations of studies on the impact of nitric oxide pathway abnormalities in both males and females will show the manner in which nitric oxide affects the endocrine pathway relating to sexual behavior for males and females.
Nitric Oxide: Physiological Pathway
Research studies show that the role of nitric oxide in sexual behavior is not a single, direct mechanism. Instead nitric oxide induces erections in males both indirectly through an endocrine pathway and directly through contact based release. Both mechanisms will be described in this analysis. Studies in rat models shows that nitric oxide release is mediated by the release of the hormone oxytocin.
The interesting thing about this relationship is that the release of nitric oxide from oxytocin release does not result in male erection directly. Instead, the release of oxytocin leads to the release of nitric oxide within the cell bodies of oxytocin dependent neurons.
These oxytocin dependent neurons have connections to hypothalamic areas of the brain, and the action potential generated by the presence of nitric oxide activates the neurons to stimulate the region of the brain influential on sexual behavior, leading indirectly to an erection in males caused by signaling from the central nervous system.
Thus one manner in which nitric oxide plays a role in sexual behavior is through acting as a secondary messenger, or neurotransmitter, with oxytocin being the primary factor setting off the increase in nitric oxide release within certain cells. In addition to oxytocin, rat models also showed a dependence on another hormone, alpha-melanocyte for male erection. The difference between the dependence on alpha-melanocyte and oxytocin in the studies was simply based on location of injection.
Oxytocin had a greater impact on nitric oxide release when injected in spinal areas while alpha-melanocyte had a greater impact on nitric oxide release when injected in areas above the spinal column. The stimulation of hypothalamic and other brain regions known to mediate sexual activity was the same however (2).
The role of nitric oxide in an endocrine pathway leading to sexual arousal has been established. Nitric oxide stimulates sexual behavior in a more direct mechanism as well however. The previous studies show that nitric oxide induces erections in males through a hormonal pathway leading to stimulation of brain areas that mediate sexual behavior.
This is only half the story though. It is shown that while the oxytocin/alpha-melanocyte based release of nitric oxide induces the beginning of an erection in male rats, a direct release of nitric oxide in the endothelial cells of the penis is what sustains an erection. Figure 1: Nitric Oxide: endothelial mechanism (2)
Studies show that direct electrical stimulation, pressure, and strain on the penis causes the release of nitric oxide by the endothelial cells, increasing and sustaining male erections after the initial release of nitric oxide within neurotransmitter cells signaling the brain to activate sexual behavior mechanisms. An important thing to take from this study, also involving human models, is that erections in males were not sustainable when the hormone mechanism activating the central nervous system described above was cut out as a variable (2).
Thus, nitric oxide that was only released from the endothelial cells in the penis did not produce the same amount of sexual arousal by itself as when combined with nitric oxide release from the hormonal pathway.
Nitric Oxide: Pathophysiology (males)
It is now important to look at studies that focus directly on the role of nitric oxide in erectile dysfunction. This analysis will not concentrate on studies that show the success and failure rates of various pharmacological treatments for erectile dysfunction, but rather will examine studies that show the dependence on nitric oxide for proper male sexual activation.
A study examining the dependence of male erectile function on the presence of nitric oxide was performed on males undergoing a prostatectomy that did not damage any of the main penile nerves. The results of the study show that three months after the surgery, none of the participants had erections. This lack of erectile function correlated to a lack of any nitric oxide in the blood circulating to the penis of these patients (cavernous blood).
The study then examined the patients again at a later time (18 months), and found that those post-surgery patients who still did not have erectile function still lacked any nitric oxide in the cavernous blood of the penis. Those patients who gained erectile function back however did show nitric oxide in the cavernous blood of the penis (3).
This study directly shows the manner in which erectile dysfunction is dependent at least partly on proper formation and release of nitric oxide in males. This study does a very good job of creating a causal link between erectile dysfunction and an abnormal nitric oxide mechanism. The study however leaves has some faults that can call this link into question.
First off, the study has a total of 14 participants. This small pool of data makes it difficult to give a high power level to the study, making the confidence interval with which the claims are made smaller than it could be. In addition, the hormonal mechanism of nitric oxide was not controlled for in this study.
A better study would monitor blood hormonal levels of the hormones such as oxytocin, known to play a role in the endocrine pathway of nitric oxide release in relation to sexual behavior. Any abnormalities in hormonal levels for this pathway could have affected the ability to retain proper erectile function in the patients used for the study. Monitoring these hormonal levels in the patients after the prostatectomy would even allow the researches to possibly find even more interesting results relating both nitric oxide pathways to erectile dysfunction in their study.
Nitric Oxide: Role in Female Sexual Behavior
The focus of most nitric oxide studies is on male erectile function. But what role does nitric oxide play in female sexual behavior? Studies show that nitric oxide also impacts female sexual behavior. A study on female rats examined the relationship between the expression of lordosis (arching of the back during sexual activity, important for many animal species), and nitric oxide.
The study examined the effects of inducing nitric oxide inhibiting agents on a female rat’s sexual response in the presence of a male rat. Data from the study shows that in the presence of vaginal stimulation, nitric oxide release triggered by the release of adrenergic hormones is necessary for the expression of lordosis.
Inhibiting the release of nitric oxide resulted in no expression of lordosis by any of the test rats (4). This study shows that nitric oxide is involved in a hormone release mechanism required for proper female sexual function as well, not just men. The fact that experiment kept vaginal stimulation of the female rats a constant gives further evidence that nitric oxide is involved in a hormonal pathway in women as well. Vaginal stimulation alone was not enough to induce lordosis in the rats, thus a nitric oxide dependent hormone pathway must be involved in the expression of lordosis.
The studies examined in this analysis show that nitric oxide is involved in an endocrine pathway in addition to a contact based release mechanism. Inhibition of production and release in the various studies caused a lack of expression of sexual related behavior in both males and females. The purpose of this analysis was to show that nitric oxide and the central nervous system are connected in regulating sexual behavior and the data from the studies supports this claim.
The growing use of sexual enhancement drugs based on the nitric oxide pathway shows the importance of examining this chemical’s role in sexual behavior. Society places a large amount of importance on adequate sexual function and furthering studies on this chemical, particularly increasing the amount of studies using female human models, would be worth while.
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1. Nelson, R.J. (2005). An introduction to behavioral endocrinology, third edition. Sunderland: Sinauer Associates.
2. Noboru Toda, Kazuhede Ayajiki and Tomio Okamura Nitric oxide and penile erectile function.
Department of Pharmacology, Shiga University of Medical Science, Otsu, Japan
Toyama Institute for Cardiovascular Pharmacology Research, 7–13, 1-Chome, Azuchi-machi, Chuo-ku, Osaka 541-0052, Japan Pharmacol Ther. 2005 May;106(2):233-66. Epub 2005 Mar 2
3. Zucchi A. Arienti G. Mearini L. Costantini E. Bini V. Porena M. Palmerini CA. Recovery of sexual function after nerve-sparing radical retropubic prostatectomy: is cavernous nitric oxide level a prognostic index?. [Journal Article] International Journal of Impotence Research. 18(2):198-200, 2006 Mar-Apr.
4. Gonzalez-Flores O. Beyer C. Lima-Hernandez FJ. Gomora-Arrati P. Gomez-Camarillo MA. Hoffman K. Etgen AM. Facilitation of estrous behavior by vaginal cervical stimulation in female rats involves alpha1-adrenergic receptor activation of the nitric oxide pathway. [Journal Article. Research Support, N.I.H., Extramural. Research Support, Non-U.S. Gov't] Behavioural Brain Research. 176(2):237-43, 2007 Jan 25.
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