Sleep Apnea as a Potential Threat to Reproduction

In the current issue of SLEEP, Torres and her colleagues¹ made an important contribution to increasing our knowledge about the relationship between obstructive sleep apnea (OSA) and male infertility. Sleep apnea is a prevalent sleep disorder, which affects up to a third of the adult population and is composed by the triad: hypoxia-reoxygenation, sleep fragmentation, and intrathoracic pressure swings.² Importantly, Torres et al. have shown for the first time that chronic high-frequency intermittent hypoxia, characteristic of OSA, reduced male fertility and testicle antioxidant capacity in middle-aged mice, accompanied by local cyclic desaturation of the reproductive tissue.¹

Torres implemented a controlled protocol that mimicked two important factors intrinsically related to modern society and OSA, respectively: the age-delay in fatherhood and the short cycles of hypoxia-reoxygenation. Motility impairment of sperm and increased oxidative stress markers were observed in the testicles from both middle-aged and young mice subjected to intermittent hypoxia, with no significant changes found in either sperm viability or concentration. The fertility parameters, assessed only in middle-aged mice, were strongly affected by intermittent hypoxia, in a sexual behavior-independent manner. Moreover, the authors found a differential fertility pattern: within the mice subjected to chronic intermittent hypoxia, those that succeeded in impregnating females presented the same rate of fetuses per littermates than those kept in normoxia during all protocol.

Previous studies using intermittent hypoxia in an animal model of OSA showed that mice submitted to chronic exposure protocols developed erectile dysfunction in association with decreased libido and impaired sexual performance.^3,4 These studies also demonstrated that intermittent hypoxia increased oxidative stress in the erectile tissue through modulation of the NADPH-oxidase enzyme, resulting in decreased nitric oxide production.^3,4 However, the study by Torres showed no changes in mating intercourse.¹ This may be explained by the fact that in their study, the animals were not trained for equal acquisition of sexual experience, which could have possibly affected the assessment of sexual behavior.⁵ It is important to note that the authors applied a faster frequency of intermittent hypoxia (20 s of 5% O₂ followed by 40 s of room air) compared to previous studies, in order to better reflect what occurs in patients with OSA. However, it is known that the adaptive or maladaptive responses to intermittent hypoxia can be generally predicted by the frequency, severity, and duration of hypoxia.⁶ Thus, this may explain at least in part the differences found between the study's results and previous literature, relative to sexual performance.

Several studies have demonstrated that 10% to 60% of OSA patients may develop erectile dysfunction as an endothelial dysfunction signal,^7,8 which in turn can be significantly improved after treatment with continuous positive airway pressure (CPAP).⁹ However, the exact underlying mechanism for this association is difficult to elucidate, since multiple factors such as obesity, systemic inflammation, sympathetic activation, and intermittent hypoxia, may play a role. In this respect, the use of animal models is very important, as it allows a translational study approach, focusing on the cause-consequence mechanisms associated with sleep related respiratory events, without some of the confounding factors that occur in human OSA.

Considering our current society, the study by Torres has potential implications. In France, a recent prospective 17-year follow-up study of a representative population sample, demonstrated that sperm quality has decreased by nearly one-third over 2 decades, or by 1.9% a year.¹⁰ Indeed, a possible “sperm crisis” may be occurring, and its link with the environment may be partially explained by the increasing incidence in sleep disturbance.^11,12 Intermittent hypoxia associated to OSA may be an important contributing factor to this sleep-fertility relationship. Future studies are needed to understand the long-term effects of intermittent hypoxia on neurobehavioral parameters in offspring, since the lack of change in the number of fetuses per littermates does not guarantee success of F1 generation. Importantly, F1 male offspring of sleep restricted or paradoxically sleep-deprived males present a reduction in the sexual response and testosterone concentrations during adulthood, while females increase proceptivity behavior compared with control offspring, showing distinct effects for each gender.¹³

Recent evidence has revealed that the increase of reactive oxygen species (ROS) in sperm itself impairs embryo, pregnancy, and offspring health, even without affecting sperm motility or fertilization, due to reduced implantation rates.¹⁴ This points to the need for further investigation to clarify whether intermittent hypoxia is implicated in elevated ROS sperm concentrations, and contributes to pre-implantation or post-implantation failures as well as programming offspring changes. A target that could be evaluated as an important ROS generator resource related to the possible mechanisms underlying reduced fertility in intermittent hypoxia is NADPH-oxidase. In addition, it is important to note that the sperm evaluated by Torres was collected from the epididymis and therefore differs significantly from ejaculation semen, and may not reflect the total environment associated with male fertility status, since it does not pass through the ejaculatory ducts, seminal vesicles, prostate, and bulbourethral glands. Especially in rodents, the semen is differentially stored, with the sperm maturation occurring in the epididymis cauda.¹⁵

Finally, as the authors noted, their study lacked the investigation of hormonal parameters such as testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and progesterone, which may play a mechanistic role in fertility. It will be valuable to determine whether intermittent hypoxia itself leads to hormonal and morphological alterations of the reproductive tract, and consequent spermatogenesis impairment in young mice; or alternatively, if the effects found are only observed when synergistically associated with aging.

In conclusion, we congratulate Torres and colleagues¹ for the important contribution this elegant study makes, which may impact future research directions in the reproductive area, leading for example, to screening men with hypogonadism and infertility for sleep apnea.

CITATION

Hirotsu C, Tufik S, Andersen ML. Sleep apnea as a potential threat to reproduction. SLEEP 2014;37(11):1731-1732.

DISCLOSURE STATEMENT

The authors have indicated no financial conflicts of interest.