Erectile dysfunction (ED) is one of the most prevalent chronic conditions affecting men. ED can arise from disruptions during development, affecting the patterning of erectile tissues in the penis and/or disruptions in adulthood that impact sexual stimuli, neural pathways, molecular changes, and endocrine signalling that are required to drive erection. Sexual stimulation activates the parasympathetic system which causes nerve terminals in the penis to release nitric oxide (NO). As a result, the penile blood vessels dilate, allowing the penis to engorge with blood. This expansion subsequently compresses the veins surrounding the erectile tissue, restricting venous outflow. As a result, the blood pressure localised in the penis increases dramatically to produce a rigid erection, a process known as tumescence. The sympathetic pathway releases noradrenaline (NA) which causes detumescence: the reversion of the penis to the flaccid state. Androgen signalling is critical for erectile function through its role in penis development and in regulating the physiological processes driving erection in the adult. Interestingly, estrogen signalling is also implicated in penis development and potentially in processes which regulate erectile function during adulthood. Given that endocrine signalling has a prominent role in erectile function, it is likely that exposure to endocrine disrupting chemicals (EDCs) is a risk factor for ED, although this is an under-researched field. Thus, our review provides a detailed description of the underlying biology of erectile function with a focus on the role of endocrine signalling, exploring the potential link between EDCs and ED based on animal and human studies.

Administration of pain relievers has been associated with both lower and higher risks of adverse reproductive outcomes in animals. In the sole investigation of male pain-reliever use and human fertility carried out to date, Smarr et al. (Hum Reprod. 2016;31(9):2119-2127) found a 35% reduction in fecundability among males with urinary acetaminophen concentrations in the highest quartile (>73.5 ng/mL) versus the lowest (<5.4 ng/mL). We analyzed data from 1,956 males participating in Pregnancy Study Online, a preconception cohort study of North American couples enrolled between 2013 and 2019. Males and females completed baseline questionnaires on sociodemographic characteristics, lifestyle, medication use, and medical history; females completed bimonthly follow-up questionnaires for up to 12 months. We categorized pain medications by active ingredient (ibuprofen, acetaminophen, naproxen, aspirin) and cumulative monthly dose. We used proportional probabilities models to calculate fecundability ratios and 95% confidence intervals, adjusting for potential confounders. In the 4 weeks before baseline, 51.7% of males used pain medications. Adjusted fecundability ratios were 1.02 for ibuprofen (95% confidence interval (CI): 0.91, 1.13), 0.89 for acetaminophen (95% CI: 0.77, 1.03), 1.07 for naproxen (95% CI: 0.85, 1.35), and 1.05 for aspirin (95% CI: 0.81, 1.35), as compared with nonuse of each medication. In this study, male use of pain medications at low doses was not notably associated with fecundability.

Ibuprofen is a commonly used non-steroidal anti-inflammatory drug that is noted for its favorable safety profile. It exerts its therapeutic effect through inhibition of prostaglandin (PG) production at inflammatory sites. However, the inhibition of PG synthesis at other sites is responsible for the occurrence of adverse events. Evidence regarding the effect of regular ibuprofen intake on penile PG homeostasis or penile histopathologic changes is lacking. The aim of this study was to examine the effect of regular administration of analgesic therapeutic doses of ibuprofen on penile PG E1 and F2α and penile microscopic changes of the treated rats. This study included four groups of adult male Wistar rats; a control group (I) injected intraperitoneally with saline (2 ml/kg/day) for 30 days and 3 ibuprofen-treated groups (IIa, IIb, and IIc) injected intraperitoneally with 6 mg/kg/day, 12 mg/kg/day, and 18 mg/kg/day ibuprofen, respectively, for 30 days, respectively. Mean levels of penile PGE1 and PGF2α in the control group were significantly higher than ibuprofen-treated groups IIa, IIb, and IIc. The percentage area of collagen around cavernous tissue was significantly higher in ibuprofen-treated groups IIa, IIb, and IIc than control rats. Our findings suggest that despite ibuprofen's safety profile, regular use of ibuprofen is associated with reduced penile PG and increased cavernosal fibrosis.

Penile erection is a perfect example of microcirculation modulated by psychological factors and hormonal status. It is the result of a complex neurovascular process that involves the integrative synchronized action of vascular endothelium; smooth muscle; and psychological, neuronal, and hormonal systems. Therefore, the fine coordination of these events is essential to maintain penile flaccidity or allow erection; an alteration of these events leads to erectile dysfunction (ED). ED is defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity. A great boost to this research field was given by commercialization of phosphodiesterase-5 (PDE5) inhibitors. Indeed, following the discovery of sildenafil, research on the mechanisms underlying penile erection has had an enormous boost, and many preclinical and clinical papers have been published in the last 10 years. This review is structured to provide an overview of the mediators and peripheral mechanism(s) involved in penile function in men, the drugs used in therapy, and the future prospective in the management of ED. Indeed, 30% of patients affected by ED are classified as "nonresponders," and there is still an unmet need for therapeutic alternatives. A flowchart suggesting the guidelines for ED evaluation and the ED pharmacological treatment is also provided.

Erectile dysfunction (ED) is very prevalent in the older population, although the ageing-related mechanisms involved in the development of ED are poorly understood. We propose that age-induced differences in nerve- and endothelium-mediated smooth muscle contractility in the corpus cavernosum (CC) could be found between a senescent-accelerated mouse prone (SAMP8) and senescent-accelerated mouse resistant (SAMR1) strains. We analysed the changes in muscle tension induced by electrical field stimulation (EFS) or agonist addition 'in vitro', assessing nerve density (adrenergic, cholinergic and nitrergic), the expression of endothelial nitric oxide synthase (eNOS), cGMP accumulation and the distribution of interstitial cells (ICs) by immunofluorescence. We observed no change in both the nerve-dependent adrenergic excitatory contractility at physiological levels of stimulation and in the nitrergic inhibitory response in SAMP8 animals. Unlike cholinergic innervation, the density of adrenergic and nitrergic nerves increased in SAMP8 mice. In contrast, smooth muscle sensitivity to exogenous noradrenaline (NA) was slightly reduced, whereas cGMP accumulation in response to EFS and DEA/NO, and relaxations to DEA/NO and sildenafil, were not modified. No changes in the expression of eNOS and in the distribution of vimentin-positive ICs were detected in the aged animals. The ACh induced atropine-sensitive biphasic endothelium-dependent responses involved relaxation at low concentrations that turned into contractions at the highest doses. CC relaxation was mainly because of the production of NO together with some relaxant prostanoid, which did not change in SAMP8 animals. In contrast, the contractile component was considerably higher in the aged animals and it was completely inhibited by indomethacin. In conclusion, a clear imbalance towards enhanced production of contractile prostanoids from the endothelium may contribute to ED in the elderly. On the basis of these data, we propose the senescence-accelerated mouse model as a reliable tool to analyse the basic ageing mechanisms of the CC.

Male sexual response is controlled by a series of neurally mediated phenomena regulating libido, motivation, arousal and genital responses such as penile erection and ejaculation. These neural events that occur in a hormonally defined milieu involve different neurophysiological, neurochemical, and neuropsychological parameters controlled by central mechanisms, spinal reflexes and peripheral nervous system. Epidemiologic studies have suggested the high prevalence of male sexual dysfunction worldwide with significant impact on the quality of life of patients suffering from this problem. The incidence of sexual dysfunction is particularly high among men with neurologic disorders. Sexual dysfunction in men, such as loss of sexual desire, erectile dysfunction (ED), changes in arousal, and disturbances in orgasm and ejaculation may involve organic causes, psychological problems, or both. Organic male sexual disorders include a wide variety of neurologic, vasculogenic, neurovascular or hormonal factors that interfere with libido, erection, ejaculation and orgasm. Neurogenic sexual dysfunction may result from a specific neurologic problem or it could be the presenting symptom of a developing neurologic disease. Neurologic ED could result from complications of chronic neurologic disorders, trauma, surgical injury or iatrogenic causes. These etiologic factors and the underlying pathophysiologic conditions could overlap, which should be considered when making a diagnosis and selecting a treatment. A detailed history of physical examination, neurologic disorders, as well as any past history of psychological and psychiatric disturbances, and a thorough neurological examination will provide better understanding of the underlying causes of neurogenic sexual dysfunction. In patients with spinal cord injury, the location of the lesion and the time of onset of injury should be determined. Therapeutic strategies against erectile dysfunction are initiated with the least invasive options using the phosphodiesterase inhibitors. When oral medication options are exhausted, intraurethral and intracavernosal therapies and ultimately vacuum constriction devices and penile implants are considered. Recent basic research has suggested the potential role of stem cell-based therapeutic strategies to protect penile neural integrity and reverse cavernosal neurodegeneration in experimental models. Further insight into the central, spinal and peripheral neural mechanisms of male sexual response may help precise diagnosis and better management of neurogenic sexual dysfunction in men.

Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, both autonomic and somatic, and supraspinal influences from visual, olfactory, and imaginary stimuli. Several central transmitters are involved in the erectile control. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropin/α-melanocyte-stimulating hormone, have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. The balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa (CC) and determines the functional state of the penis. Noradrenaline contracts both CC and penile vessels via stimulation of α₁-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and CC. The role of other mediators, released from nerves or endothelium, has not been definitely established. Erectile dysfunction (ED), defined as the "inability to achieve or maintain an erection adequate for sexual satisfaction," may have multiple causes and can be classified as psychogenic, vasculogenic or organic, neurologic, and endocrinologic. Many patients with ED respond well to the pharmacological treatments that are currently available, but there are still groups of patients in whom the response is unsatisfactory. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including oral phosphodiesterase inhibitors and intracavernosal injections of prostaglandin E₁. Irrespective of the underlying cause, these drugs are effective in the majority of cases. Drugs with a central site of action have so far not been very successful. There is a need for therapeutic alternatives. This requires identification of new therapeutic targets and design of new approaches. Research in the field is expanding, and several promising new targets for future drugs have been identified.

Sexual function in men and women incorporates physiologic processes and regulation of the central and peripheral nervous systems, the vascular system, and the endocrine system. There is need for state-of-the-art information as there is an evolving research understanding of the underlying molecular biological factors and mechanisms governing sexual physiologic functions.

To develop an evidence-based, state-of-the-art consensus report on the current knowledge of the major cellular and molecular targets of biologic systems responsible for sexual physiologic function.

State-of-the-art knowledge representing the opinions of seven experts from four countries was developed in a consensus process over a 2-year period.

Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate.

Scientific investigation in this field is needed to increase knowledge and foster development of the future line of treatments for all forms of biological-based sexual dysfunction. This article addresses the current knowledge of the major cellular and molecular targets of biological systems responsible for sexual physiologic function. Future treatment targets include growth factor therapy, gene therapy, stem and cell-based therapies, and regenerative medicine.

Scientific discovery is critically important for developing new and increasingly effective treatments in sexual medicine. Broad physiologic directions should be vigorously explored and considered for future management of sexual disorders.

Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through alpha(1)- and alpha(2)-postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through alpha(2)-presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y(1)- and Y(2)-postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of alpha(1)-adrenoceptors involves both Ca(2+) influx through L-type and receptor-operated Ca(2+) channels (ROC) and Ca(2+) sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca(2+) entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3'-monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K(+) efflux through Ca(2+)-activated (K(Ca)) and voltage-dependent Ca(2+) (K(v)) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca(2+) sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K(+) efflux through ATP-sensitive K(+) (K(ATP)) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitation-secretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.

Erectile dysfunction (ED) is defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity (2nd International Consultation on Sexual Dysfunction-Paris, June 28th-July 1st, 2003). Following the discovery and introduction of sildenafil, research on the mechanisms underlying penile erection has had an enormous boost and many preclinical and clinical papers have been published in the last 5 years. This review is structured in order to give the reader an overview of the clinical and preclinical data available on the peripheral regulation of and the mediators involved in human penile erection. The most widely accepted risk factors for ED are discussed. The article is focused on human data, and the safety and effectiveness of the 3 commercially available Phosphodiesterase-5 (PDE5) inhibitors used to treat ED are also discussed.

In the absence of arousal stimuli, the activity of the Rho-kinase-mediated signaling pathway promotes vasoconstriction of the cavernosal arterioles and sinuses, keeping the penis in the nonerect state. Upon sexual arousal or during nocturnal tumescence, nitric oxide (NO), released from nonadrenergic/noncholinergic nerves or from local endothelial cells, induces cavernosal vasodilation, resulting in an elevation in blood flow and intracavernosal pressure to initiate the erectile response. Although NO is thought to be the principal stimulator of penile erection, the signaling mechanism(s) of NO-mediated cavernosal vasodilation is unknown. In this article, we will consider the novel hypothesis that NO induces penile erection through the inhibition of endogenous Rho-kinase-mediated vasoconstriction. Additionally, we will look downstream of Rho-kinase, introducing a potential role for various substrates in the mechanism of Rho-kinase-mediated constriction in the cavernosal vasculature.

The incidence of erectile dysfunction increases with diabetes, hypertension, hypercholesterolaemia, cardiovascular disease and renal failure. All these conditions are associated with endothelial dysfunction. This review addresses the pathophysiology of erectile dysfunction with a special focus on new insights into nitric oxide (NO)-mediated pathways, oxidative stress and parallels to endothelial dysfunction. NO appears to be the key mediator promoting endothelium-derived vasodilation and penile erection. The possibility is discussed that elevated plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, may provide an additional pathomechanism for various forms of erectile dysfunction associated with cardiovascular risk factors and disease. Likewise, the role of endothelium-derived factors mediating NO-independent pathways is evaluated.

To investigate the interaction of endothelium-derived nitric oxide (NO) and prostaglandins (PGs) in regulating corporal smooth muscle tone in vitro. Materials and methods Strips of rabbit corpus cavernosum were mounted in organ chambers for the measurement of isometric tension. Strips were submaximally contracted with noradrenaline and concentration-response curves (CRCs) to acetylcholine (ACh) were constructed before and after treatment with 5 micromol/L atropine, 20 micromol of the cyclooxygenase inhibitor indomethacin and 10 micromol of the PGH2/thromboxane A2 receptor antagonist SQ29548. The NO synthase (NOS) inhibitors L-NG-monomethyl arginine (L-NMMA) and L-NG-nitroarginine (L-NOARG) were added to strips at tonic tension in the presence and absence of indomethacin, and after this CRCs to ACh were constructed.

The addition of ACh to strips produced a concentration-dependent relaxation which was inhibited by atropine. Indomethacin, but not SQ29548, significantly increased relaxation to ACh. Relaxation to ACh was impaired by L-NMMA, but adding ACh to strips treated with L-NOARG resulted in contractile responses, whilst both effects were reversed by indomethacin. L-NMMA and L-NOARG led to increases in tonic tone which were unaffected by indomethacin.

In rabbit corpus cavernosum there is a tonic release of NO which does not appear to be inhibited by a vasoconstrictor prostanoid. Endothelium-dependent relaxation to ACh results in the dual production of NO and a cyclooxygenase-derived endothelium contracting factor which acts in opposition to NO; this factor is unlikely to act on PGH2/TXA2 receptors.