ED in Men on the Rise: Is There a Link with Endocrine Disrupting Chemicals?

[madman]

Abstract

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 signaling is also implicated in penis development and potentially in processes that 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.




Erectile Dysfunction

Erectile Dysfunction Erectile Dysfunction (ED) is defined as the consistent or repeated inability to acquire or sustain an erection sufficient for satisfactory sexual performance [McCabe et al., 2016]. The 5-item International Index of Erectile Function (IIEF-5) self-questionnaire categorizes the severity of ED based on the numerical score (each of the 5 questions is worth 5 points) as no ED (22–25), mild (17–21), mild to moderate (12–16), moderate (8–11), or severe (1–7) [Rhoden et al., 2002]. The erectile function relies on a combination of organic (structural, neurologic, vascular, and endocrine) and psychogenic factors. Thus, ED can have a number of aetiologies that are broadly classified as either organic or psychogenic [Johannes et al., 2000]. Psychogenic risk factors for ED include depression and anxiety [Yang et al., 2019], although these are beyond the scope of this review. Organic risk factors include vascular, neurologic, and endocrine abnormalities [reviewed in Ludwig and Phillips, 2014]. Interestingly, since the penile vascular tissue that is responsible for an erection is a component of the global vascular system, ED of vascular origin is often an indicator of systemic endothelial dysfunction [Virag et al., 1981]. Thus, ED not only disrupts the quality of life but can also be a strong indicator of cardiovascular disease [Gandaglia et al., 2014].


Physiology of Erectile Function
-Neural Stimulation

-Anatomy, Vasculature, and Hemodynamics of Erection
-Calcium-Mediated Penile Smooth Muscle Contraction/Relaxation and RhoA/Rho KinaseMediated Calcium Sensitisation
-Nitric Oxide (NO)-cGMP Mediated Tumescence
-NO Production by Activation of Nitric Oxide Synthase Isoforms
-Disruptions of NO-cGMP Pathway and Compensatory Mechanisms

-Additional Pro-Erectile Signalling Pathways
-cAMP/PKA Pathway
-Vasoactive Intestinal Peptide
-Prostanoids (Involved in Tumescence and Detumescence)
-Acetylcholine
-Noradrenaline-Mediated Detumescence

-Other Signalling Pathways Involved in Detumescence
-Endothelin-1
-Angiotensin II


*Link between Endocrine Disrupting Chemicals and Erectile Dysfunction
-Effects of Estrogenic-EDCs and Endogenous Estrogen Signalling on Erectile Function
-Indirect and Direct Mechanisms for ED Induced by Estrogenic-EDCs
-Potential Role of EDCs in Human ED and Other Aspects of Male Reproductive Health




Conclusion

ED is extremely prevalent globally and presents major lifestyle and health problems for affected individuals and their partners. The rapid increase in prevalence cannot be accounted for by genetics and age alone; environmental factors must also play a role. Thus, it is critical to understand this condition and the underlying biology of erectile function. This review summarised the complex interplay between neural, vascular, molecular, and hormonal mechanisms which govern erectile function; disruptions to any of these factors are considered risk factors for ED. However, the role of EDCs as risk factors for ED is starkly under-researched. This is despite established knowledge that androgens and potentially endogenous estrogens are both critical for erectile function in both developmental and adult physiological contexts, EDCs are pervasive in our environment, and multiple animal studies strongly suggest EDCs are among the risk factors for human ED. Thus, this area needs far greater attention in order to reduce ED prevalence and avert the plethora of health hazards presented by EDCs.

 

[Nelson Vergel]

The effect of endocrine disruptors on the reproductive system

Abstract OBJECTIVE: Chemicals that disrupt the endocrine homeostasis of the human body, otherwise known as endocrine disruptors (EDCs), are found in the blood, urine, amniotic fluid, or adipose tissue. This paper presents the current knowledge about EDCs and the reproductive system. MATERIALS...

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[Nelson Vergel]

Reducing Adult Exposure to Phthalates

Phthalates are known hormone disruptors and have been shown to lower testosterone levels in men and increase the risk of breast cancer in women. A surprising source of phthalates is sexual lubricants: It turns out that “jelly” is plasticized PVC—up to two-thirds phthalates by weight. Though...

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[madman]

Fig. 1. Transverse section of an adult human penis [Yafi et al., 2016]. The corpus cavernosum (paired) and corpus spongiosum constitute the 3 erectile tissues of the penis. The tunica albuginea surrounds the corpora cavernosa. Blood flows into the corpus cavernosum via the cavernous artery, which branches into helicine arteries that supply the sinusoidal spaces. Blood drains from the sinusoidal spaces into the subtunical plexus, which forms the emissary vein that passes through the tunica albuginea. Emissary veins drain directly into the deep dorsal artery or into the circumflex veins which also drain into the deep dorsal artery. The dorsal nerve is a sensory somatic nerve fiber responsible for reflexogenic erections.

 

[madman]

Fig. 2. Androgen regulation of erectile tissue and molecular signalling involved in erectile physiology. Androgen signalling maintains non-adrenergic, non-cholinergic (NANC) nerve fibre and smooth muscle levels in the erectile tissue. Androgens also activate K+ channels in smooth muscle, and androgen levels correlate with voltage-gated Ca2+ channel expression in the smooth muscle of the erectile tissue. Androgens positively regulate phosphodiesterase 5 (PDE5) in the smooth muscle and nitric oxide synthase (NOS) enzymes, which are localised NANC nerves and endothelial cells

 

[madman]

Fig. 3. MLCK and MLCP mediate smooth muscle contraction and relaxation, respectively [Mas, 2010]. Ca2+ ions bind to calmodulin to form the Ca2+-calmodulin complex (Cam-Ca) which then binds to and activates MLCK. Active MLCK phosphorylates MLC, facilitating smooth muscle contraction. Conversely, active MLCP dephosphorylates MLC, causing smooth muscle relaxation and tumescence. Active RhoA activates Rho kinase which deactivates MLCP by phosphorylation. Inactive RhoA allows for the activation of MLCP. Green refers to pathways driving tumescence, red refers to that of detumescence. MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; MLC, myosin light chain; Cam-Ca, Ca2+-calmodulin complex; P, phosphate group

 

[madman]

Fig. 4. NO-cGMP mediated smooth muscle relaxation. Extracellular nitric oxide (NO) diffuses through the smooth muscle cell membrane and activates soluble guanylyl cyclase (sGC), producing cGMP as a result. This activates protein kinase G (PKG) which then activates K+ channels causing an efflux of K+ from the cell. This results in hyperpolarization (HP) which blocks Ca2+ channels so Ca2+ influx is reduced. In addition, PKG also activates cation ATPase pumps in the cell membrane and sarcoplasmic reticulum (SR), driving an efflux of Ca2+ out of the cell and sequestration of Ca2+ in the SR, respectively. PKG also suppresses the RhoA/Rho-kinase pathway, thereby decreasing Ca2+ sensitivity. NO-mediated reduction in cytosolic Ca2+ and increased Ca2+ sensitivity drives relaxation of the smooth muscle cell. The phosphodiesterase proteins (PDEs) break down cGMP.

 

[madman]

Fig. 5. Estrogen-mediated positive regulation of eNOS expression/activation. In the endothelial cell, when the estrogen receptor (ER) binds to the estrogen ligand (endogenous or exogenous estrogen or estrogen-mimicking EDCs; green circle), it dimerizes and translocates to the nucleus where it binds to an estrogen-response element (ERE) in the NOS3 promoter. This induces transcription of NOS3 which leads to the production of endothelial nitric oxide synthase (eNOS). In addition, the association of membrane-bound estrogen receptors (mERs) with estrogen initiates rapid, non-genomic signaling. This involves activation of the phosphoinositide 3-kinase/ protein kinase B (PI3K/Akt) pathway, which in turn activates eNOS by phosphorylation so that it produces NO. NO is the same as shown in Figure 4

 

[madman]

Fig. 6. NO sources and other factors which drive smooth muscle relaxation. The NO-cGMP pathway reduces cytosolic Ca2+ and inhibits the RhoA/Rho-kinase pathway as depicted in Figure 4. When the NANC nerves are stimulated (lightning bolt), Ca2+ binds to calmodulin to form the calmodulin-Ca2+ (Cam-Ca2+) complex. This subsequently binds to and activates neuronal NOS (nNOS), driving NO production. Also, stimulation of NANC nerves drives the production of cAMP in these cells. This activates protein kinase A (PKA) which in turn activates nNOS by phosphorylation (P). The initial production of NO by the NANC nerves leads to smooth muscle cell (SMC) relaxation, in turn leading to shear stress on the endothelial cells. This triggers the PI3K/Akt pathway, which then activates eNOS by phosphorylation. Acetylcholine released from cholinergic nerves binds to the muscarinic acetylcholine receptor (mAChR), which increases Ca2+ in the endothelial cell. This leads to the formation of Cam-Ca2+, which binds to and activates eNOS. Endogenous estrogen signaling also activates eNOS by stimulating the PI3K/Akt pathway and upregulating the expression of eNOS (see Fig. 5). In addition to the NO-cGMP pathway, vasoactive intestinal peptide (VIP) in the NANC nerves may bind to its receptor (VIP-R) on the smooth muscle cell to stimulate soluble adenylyl cyclase (sAC). This leads to the production of cAMP in the smooth muscle cell, activating PKA to reduce cytosolic Ca2+ concentration. cAMP may also mediate smooth muscle cell relaxation via activation of PKG. The prostanoids prostaglandin E2 (PGE2) and prostacyclin (PGI2) can also drive cAMP production via association with the EP and IP receptors on the smooth muscle cell, respectively. NANC is the same as shown in Figure 2sGC, PKG and NO are the same as shown in Figure 4. PI3K/Akt and eNOS are the same as shown in Figure 5.

 

[madman]

Fig. 7. Smooth muscle contraction pathways. Upon stimulation of adrenergic nerves (lightning bolt), noradrenaline (NA) is released and binds to the α1-adrenoreceptor (α1). Endothelin-1 (ET-1), angiotensin-II (Ang-II), and the prostanoid thromboxane A2 (TXA2) released from the endothelial cell bind to their receptors ETA, AT1, and TP, respectively, on the smooth muscle cell. Association of these ligands with their receptors leads to activation of phospholipase C (PLC), which then produces inositol triphosphate 3 (IP3) and diacylglycerol (DAG). IP3 is associated with the IP3 receptor (IP3R) on the sarcoplasmic reticulum (SR), which acts as a channel to release Ca2+ from the SR. The activated IP3Rs couple with membrane-bound transient receptor potential canonical 3 (TRPC3) channels, leading to an influx of extracellular Ca2+. Increased cytosolic Ca2+ in the smooth muscle cell causes depolarization (DP), activating Ca2+ channels in the smooth muscle cell membrane which leads to a further influx of Ca2+. DAG leads to activation of protein kinase C (PKC), which activates CPI-17 by phosphorylation. This then inhibits MLCP. Association of NA, ETA, Ang-II, and TXA2 with their receptors may also drive the RhoA/Rho-kinase pathway to inhibit MLCP. Thus, these signaling factors drive smooth muscle cell contraction by increasing cytosolic Ca2+ and increasing Ca2+ sensitivity. MLCP is the same as shown in Figure 3.