The correlation between urinary 5-hydroxyindoleacetic acid and sperm quality in infertile men and rotating shift workers

Standard parameters evaluated, i.e. sperm morphology and motility, have shown different associations with male fertility. Particularly, Zhang et al. [1] demonstrated significant correlations among in vitro semen tests (total sperm concentration and motile sperm), zona pellucida-binding assay, and in vitro blastocyst production. On the other hand, the integrity of the plasma membrane reflects sperm viability and several process related to sperm physiology, such as capacitation, acrosome reaction, and binding of spermatozoa to the oocyte surface, require a biochemically active membrane [2, 3]. Considering that capacitated and/or acrosome- reacted spermatozoa have a limited life span [4], this would result in impaired fertility.

The major function of the circadian system is the internal cycling of physiologic and metabolic events. Circadian rhythms are synchronized to the 24-h day, mostly by light-dark cycles, partially by other environmental and social time cues [5, 6]. The circadian rhythm can get desynchronized in rotating shift workers since their night activity is out of phase, and such desynchronization may contribute to important health problems. For instance, the effects of rotating and night shift work on female fertility have been reported [7]. Additionally, undergoing night shift work may alter secretion circadian rhythms, including serotonin secretion [8].

Serotonin is a neurotransmitter involved in a wide range of behavioural and physiological processes. In fact, serotonergic neurons play an important role modulating neuroendocrine functions such as food intake, sleep, mood and sexual behaviour [9]. In the male reproductive system, serotonin might affect directly sperm maturation since the existence of a local serotonergic system in the rat caput epididymis have been described [10]. However, relatively recent studies have reported that hyperserotoninaemia may relate to certain kinds of male infertility [11, 12]. In this regard, several studies have pointed out that selective serotonin reuptake inhibitors, which are commonly prescribed as antidepressants, can impair semen quality and damage sperm DNA integrity [13, 14]. Therefore, up to now, the relationship between serotonin and male fertility still remains unclear. To this end, we aimed to evaluate whether the levels of urinary 5-hydroxyindoleacetic acid (5-HIIA), a major serotonin metabolite, correlate with different seminal parameters, including sperm concentration, motility and morphology, in a set of individuals attending infertility counselling. On the other hand, we checked the relationship between male infertility and urinary 5-HIIA levels in night shift workers by comparing 5-HIIA levels and seminal parameters between a group of recent fathers and another of infertile men, all of them undergoing night shift work.

Figure 1 shows the correlations between urinary 5-HIIA levels, obtained from 20 volunteers, and different seminal parameters analysed in fresh ejaculates. Curiously, urinary 5-HIIA levels negatively correlate with sperm concentration (statistically significant), forward motility (statistically significant), morphology normal range (statistically significant) and sperm vitality (statistically significant). Taken together, these findings point out that elevated urinary 5-HIIA levels may worsen sperm quality, contrary to our expectations.

To verify whether urinary 5-HIIA levels may influence sperm quality, we compared urinary 5-HIIA levels found in urines (19:00 h) from recently-proven fathers (n = 10), designed as fertile, with those obtained from infertile males (n = 10). All volunteers were working the night shift work, which is one of the facts that may alter serotonin circadian secretion [4]. Interestingly, urinary 5-HIIA levels measured in recently-proven fathers are lower (Figure 2, statistically significant) than those found in infertile males. In addition, we further investigated the relationship between serotonin and sperm quality by comparing different seminal parameters in both fertile and infertile night shift workers (Table 1). Our results display that samples from recently- proven fathers exhibit a higher sperm concentration (statistically significant), an increased forward motility (statistically significant), as well as an elevated normal morphology rate (statistically significant), compared with those values obtained in samples from infertile males. No differences were found with regards to sperm vitality (unpublished data). Therefore, the elevated serotonin endogenous levels, indirectly assessed as urinary 5-HIIA, may impair sperm quality, thus inducing male infertility in night shift workers.

Male reproduction is likely controlled, at least partly, by circadian system. In fact, melatonin, an indoleamine whose production is subject to circadian rhythms with high levels at night and low by day [18], is able to modulate the reproductive physiology due to the melatonin regulator effect on the hypothalamus-pituitary-testicular axis [19]. Likewise, it has been reported that melatonin positively affects sperm physiology and may strongly protect spermatozoa from the oxidant environment produced by excessive round cells in seminal fluid [20, 21].

Over the past few years, studies have proven that serotonin, another component of the circadian system, is necessary for the development of normal spermatogenesis in rats [22] owing to the existence of a local serotonergic system in the rat epididymis [10]. Nevertheless, as above-mentioned, high levels of serotonin appear to play a role as an infertility determinant in male subjects suffering from varicocele [12], or even azoospermy [23], i.e. an excess of circulating serotonin may induce harmful effects on male reproductive system. In fact, long-term treatments with antidepressants which enhance the availability of endogenous serotonin, such as sertraline or citalopram, can impair semen quality [13, 14]. Despite both rats and human beings are mammals, we cannot assume that serotonin plays the same role on male reproductive system in both species because serotonin, which is also involved in sleep control [9], differently affects sleep/wake patterns in rodents and humans. In this sense, our findings shed some light on the relationship between serotonin and male infertility since we showed that the levels of urinary 5- HIIA negatively correlate with semen quality, as assessed by sperm concentration, motility or morphology.

To sum up, elevated serotonin endogenous levels, indirectly assessed as urinary 5-HIIA, likely induce poor sperm quality that, consequently, leads to subfertility problems. In the light of these results, it is feasible to presume that a high dose of serotonin locally applied to the testicular surrounding area would be used as a reversible, cost-effective male contraceptive method. However, further studies are required to clarify molecular mechanisms through which serotonin modulates male reproductive system and to test whether serotonin supplementation has any noticeable side effect, such as sexual dysfunctions or mood changes.