The role of hypoxia in erectile dysfunction mechanisms

Abstract

Chronic hypoxia is related to many pathological conditions: aging, heart and respiratory failure, sleep apneas, smoke, chronic obstructive pulmonary disease (COPD), diabetes, hypertension and arteriosclerosis, all characterized by reductions of sleep-related erections (SREs) and by erectile dysfunction (ED). Sleep-related erections occur naturally during rapid eye movement (REM) sleep in sexually potent men. Hypoxia is also a physiological condition at altitude. The level of inspired oxygen decreases progressively with the increase of altitude; for this reason, this study was performed to evaluate the relationship of SREs with hypoxic environment. SREs have been recorded by an erectometer (RigiScan) on three mountain climbers (mean age: 32.5) during a 26-day stay at an altitude ranging from 2000 to 5600 m above sea level. Twenty-four records have been made at progressively increasing altitudes. A data analysis was carried out on a statistical mean of the three values of each variable and an analysis of variance (ANOVA) and Newman–Keuls test were carried out for multiple comparison among groups. At altitudes over 4450 m, we found lack of rigidity at 80–100% and 60–79%. Mean % of rigidity and rigidity time of 80–100% (tip and base) decreased progressively with altitude. No significant reductions were shown in rigidity time at 0–19% and at 20–39% (tip and base), of total number, of total and mean duration of SREs. Pathological rigidometric records at high altitude in sexually potent men at sea level clarify the primary role of hypoxia in physiopathological ED pathway.

Introduction

SREs (sleep-related erections) are involuntary physiological phenomenon that occur in healthy men 4–5 times a night during rapid eye movement (REM) sleep phase, each of 30–45 min for a total of 80–180 min.1

The physiological role of SREs is not completely known, probably they play a role in metabolic processes at the base of erectile function and in corpus cavernosum perfusion and oxygenation.2

In fact, recent trials have shown that nitric oxide (NO) synthesis and functional integrity of penis smooth muscles depend on an adequate oxygen supply.3, 4 It still has to be cleared if SRE reductions are due to endocrinological disorders or exposure to a hypoxic environment.1

Erections are hemodynamic events caused by penile arteries dilatation and smooth muscle fiber relaxation: result of neurological, neurochemical and endocrine mechanisms.5, 6 During the flaccidity phase, sympathetic innervation causes a tonic contraction of arteries and smooth muscular cells, thus reducing blood flow. Central and/or sensorial stimuli increase vascular flow of cavernous and helicine arteries inducing erection. The following block of venous drainage, owing to compression of under-albuginea veins, with following reduction of arterial flow (5–10 ml/min) leads to a significant increase of intracavernosal pressure (150–170 mm Hg): rigidity phase. Further contraction of ischiocavernous muscles leads to an intracavernosal pressure increase (up to 200 mm Hg): maximum rigidity phase.7 The relaxation of corpus cavernosum smooth muscles is due to a nonadrenergic–noncholinergic nervous system (NANC) mediated by a neurotransmitter: NO released from nerve terminals and from endothelial cells after nervous stimulation.8, 4 Nitric oxide is a gas that diffuses into target tissues where it activates guanylate cyclase and catalyzes the formation of cyclic guanosine-3′,5′-monophosphate (cGMP) from guanosine-5′-triphosphate. cGMP initiates a cascade of intracellular events and reduces intracellular calcium which leads to relaxation of penis smooth muscles.9 Nitric oxide synthesis is mediated by NO synthetase, which requires both L-arginine and oxygen as substrates. Oxygen is involved in penis erection mechanism through regulation of NO synthesis in the corpus cavernosum tissue and through the regulation of other vasoactive substances.10, 11 Vasoconstrictor substances prevail when there are low O2 tensions, while there is a prevalence of NO and prostaglandin E1 (PGE) when there are high O2 tensions.3, 12 Low O2 tensions can interfere with NO synthesis and secretion or alter its availability upon release. Moreover, it is possible that the target cell (the smooth muscle), under hypoxic conditions, is less responsive to NO. Thus low O2 tensions can inhibit the relaxation of trabecular smooth muscle. A direct demonstration of regulation role of oxygen is provided by the measurement of NO synthase activity in rabbit corpus cavernosum cytosol preparations. Hypoxia causes a significant reduction of NO synthase activity. This suggests that oxygen can be a rate-limiting factor for NO production in the penile corpus cavernosum.13, 14

Acute hypoxia increases the afferent sympathetic activation15, 16 which increases vasoconstriction activity.17 Some studies have shown that even the acclimatization is followed by the maintenance of sympathetic excitation.18, 19 In fact, after a period of 4 weeks at 5760 m of altitude (Chacaltaya, Bolivian Andes) and some days after coming back to sea level, the sympathetic activity is higher with respect to basal levels. Mechanisms of sympathetic hyperactivity after hypoxic exposure can be related to chemoreceptors activation and sensitization and to cardiopulmonary baroreceptors activation. However, the mechanisms through which the acclimatization to hypobaric hypoxia cause a persistent activation of sympathetic nerve system are still to be clarified.20

High-altitude hypoxia is a condition characterized by reduction of partial O2 pressure, direct consequence of barometric pressure reduction, and can be used as a model of study of hypoxia condition. Many pathologic conditions, due to cardiovascular and respiratory diseases, cause conditions of hypoxic hypoxia like exposure to hypobaric hypoxia.

SREs have been studied under different pathologic conditions and in aging. The presence of a hypoxic substrate in comorbidity factors of erectile dysfunction (ED) such as diabetes, smoking, hypertension, cardiovascular diseases, chronic obstructive pulmonary disease (COPD), sleep apneas and aging indicates a correlation between chronic hypoxia and reduction of SREs.

Aging represents the main ED risk factor showing an exponential increase: 2% up to 30 years; 16% over 50 years; and 48% over 70 years.21 Another ED risk factor is diabetes: SREs are less frequent and have a reduction of maximum circumference, a shorter duration and a smaller rigidity in diabetics.22 Men with cardiovascular diseases have SREs with reduced total tumescence time.1 Incidence of ED in non-smokers is 0.3% versus 11% in smokers23 in which SREs have shown smaller penile rigidity, a lower total tumescence time and a quicker detumescence.12 Decrements of SREs have been detected also in patients with COPD.24 Patients with multiple cardiovascular disease have an increased risk of ED. Men having ED and diabetes, hypertension and/or obesity have a smaller maximum rigidity during SREs than patients having ED without these comorbidity factors.25 A high-prevalence ED is shown also in men having sleep apneas.22

The aim of the study is to evaluate the effects of high-altitude hypoxia on SREs in healthy subjects in order to evaluate the role of chronic hypoxia in SRE reductions and ED.

Materials and Methods

SREs were recorded by an erectometer (RigiScan) on three mountain climbers (mean age: 32.5) during a 26-day stay at an altitude ranging from 2000 to 5600 m above sea level (Karakorum-Baltoro Expedition 2004). All procedures were performed subsequent to informed consent and in accordance with Bioethical Committee, Chieti University. Control recording carried out before hypoxic exposure at sea level showed normal nocturnal penile tumescence and rigidity (NPTR) recording. Twenty-four records were made at progressively increasing altitudes. The control after chronic exposition was made after 1 month at sea level. Variables studied are as follows: mean rigidity % (tip and base); time of rigidity at 80–100, 60–79, 40–59, 20–39 and at 0–19% (tip and base); total number, total and mean duration of SREs. The data analysis was carried out on a statistical mean of each variable. Analysis of variance (ANOVA) and Newman–Keuls test were carried out for multiple comparison among groups. Differences among means were considered statistically significant for P<0.05.

Results

At altitudes of over 4450 m, we found a lack of rigidity at 80–100 and 60–79%. Mean of event rigidity % (tip and base) decreased up to 4000 m (P<0.05) and over 4450 m (P<0.001) (Figure 1). Rigidity time of 80–100% at base decreased over 3000 m (P<0.001) and at tip decreased up to 3000 m (P<0.05) and up to 4000 m (P<0.01) (Figure 2). No significant reductions were shown in rigidity time at 0–19, 20–39 and 40–59% (tip and base) (Figure 3), in total number, in mean and total duration of SREs. After exposition in all three subjects, there was a ‘restitutio ad integrum’ of NPTR recording. (Figures 4 and 5).

Figure 1
figure1

Base and tip mean event rigidity % of sleep-related erections in progressive altitude (ANOVA, P<0.0005). Mean of event rigidity % (tip and base) decreased up to 4000 m (P<0.05) and over 4450 m (P<0.001). The data analysis has been carried out on a statistical mean of rigidity % values. Differences among means were considered statistically significant for P<0.05.

Figure 2
figure2

Mean time rigidity 60–100% at base and tip of sleep-related erections in progressive altitude (ANOVA, P<0.0001). Rigidity time of 80–100% at base decreased over 3000 m (P<0.001) and at tip decreased up to 3000 m (P<0.05) and up to 4000 m (P<0.01).

Figure 3
figure3

Mean time rigidity 0–59% at base and tip of sleep-related erections in progressive altitude (no significant reductions were shown in rigidity time at 0–59%).

Figure 4
figure4

Mean event rigidity % at base and tip of sleep-related erections at sea level altitude. Control recordings were carried after chronic hypoxic exposure at sea level.

Figure 5
figure5

Mean time rigidity at base and tip of sleep-related erections at sea level altitude. Control recordings were carried after chronic hypoxic exposure at sea level.

Conclusions

Hypoxia increases the afferent sympathetic activation increasing vasoconstriction activity and causes a significant reduction of NO synthase activity: a rate-limiting factor for NO production in the penile corpus cavernosum.

SREs have been studied under different pathologic conditions and in aging. The presence of a hypoxic substrate in comorbidity factors of ED indicates a correlation between chronic hypoxia and reduction of SREs.

NPTR measurement performed by an erectometer (RigiScan) is considered the standard method for differential diagnosis between psychogenic and organic ED.26

An NPTR outline with at least an erectile episode characterized by 60% rigidity at both base and tip for at least 10 min is considered to be normal.27 Total lack of rigidity at 60–79% at altitudes higher than 4450 m in individuals that are healthy and strong at sea level shows the key role played by chronic hypoxia in the reduction of erythrocyte sedimentation rates. Thus, among the aspects involved in the erection physiology, the oxygen supply finds a place in the complex ED pathway.

Further studies are needed to understand the role of chronic hypoxia in physiopathologic mechanisms of ED tied to comorbidity factors such as aging, heart and breathing insufficiencies, sleep apneas, smoke, COPD, diabetes, hypertension and arteriosclerosis.

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Acknowledgements

This work was partially supported by Professor R Tenaglia and C Di Giulio.

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Correspondence to V Verratti.

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Verratti, V., Di Giulio, C., Berardinelli, F. et al. The role of hypoxia in erectile dysfunction mechanisms. Int J Impot Res 19, 496–500 (2007). https://doi.org/10.1038/sj.ijir.3901560

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Keywords

  • erectile dysfunction
  • hypoxia
  • sleep-related erections
  • altitude

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