STUDY QUESTION: Do mild analgesics affect the endocrine system of the human adult testis? SUMMARY ANSWER: Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro. WHAT IS KNOWN ALREADY: Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line. STUDY DESIGN, SIZE, DURATION: Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods. MAIN RESULTS AND THE ROLE OF CHANCE: The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play. LIMITATIONS, REASONS FOR CAUTION: Our studies were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes.

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Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro

Paracetamol and NSAIDs, in particular acetylsalicylic acid (aspirin) and ibuprofen, are among the most used and environmentally released pharmaceutical drugs. The differences in international trends in the sale and consumption of mild analgesics reflect differences in marketing, governmental policies, habits, accessibility, disease patterns and the age distribution of each population. Biomonitoring indicates ubiquitous and high human exposure to paracetamol and to salicylic acid, which is the main metabolite of acetylsalicylic acid. Furthermore, evidence suggests that analgesics can have endocrine disruptive properties capable of altering animal and human reproductive function from fetal life to adulthood in both sexes. Medical and public awareness about these health concerns should be increased, particularly among pregnant women.

Analgesic use — prevalence, biomonitoring and endocrine and reproductive effects

Introduction: The aim of this study was to evaluate the effect of selective serotonin reuptake inhibitors (SSRIs) on testicular tissue and serum malondialdehyde (MDA) levels in rats. Materials and methods: A total of 40 male Wistar albino rats, 5.5-6 months old, were equally divided at random into five groups: group 1 was the control group, group 2 received sertraline 10mg/kg (p.o), group 3 was administered fluoxetine 10mg/kg (p.o), group 4 received escitalopram 10mg/kg (p.o), and group 5 (n = 8) was administered paroxetine 20mg/kg. Each dose was administered orally for two months. Johnsen’s criteria were used to categorize spermatogenesis. Johnsen’s method assigns a score of 1 to 10 to each tubule cross-section examined. In this system, a Johnsen score of 9 and 10 indicates normal histology. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were evaluated. Serum MDA levels were also measured. Results: The mean Johnsen scores were 9.36 ± 0.33, 9.29 ± 0.32, 8.86 ± 0.48, 9.10 ± 0.56, and 8.33 ± 0.90 in control group, sertraline group, fluoxetine group, escitalopram group, and paroxetine group, respectively. The Johnsen score was significantly lower for paroxetine group compared with the control group (p < 0.05). The mean FSH level increased only in the sertraline group. With the exception of the fluoxetine group, the testosterone levels were lower in all groups compared with the control group. The total testosterone level was significantly lower in the sertraline group compared with the control group [40.87 (22.37-46.8) vs. 15.87 (13.53-19.88), p < 0.01]. There were no significant differences between the groups with respect to the MDA and LH levels (p = 0.090 and p = 0.092). Conclusion: These data suggest that SSRIs have a negative effect on testicular tissues. This negative impact is markedly greater in the paroxetine group. To determine the exact mechanism of action of these drugs on testicular tissue, well-designed randomized controlled clinical studies are needed on a larger population.

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The effect of Sertraline, Paroxetine, Fluoxetine and Escitalopram on testicular tissue and oxidative stress parameters in rats

Internal spermatic vein prostaglandins in varicocele patients

The inflammatory response is a beneficial process, but inflammatory injury of male accessory sex organs can reduce fertility by the following pathophysiological mechanisms: increased sperm agglutination (Derrick and Dahlberg 1976); reduced sperm motility and viability (Eliasson 1975); and obstruction of the ejaculatory ducts (Pomerol 1978) Disturbances in epididymal sperm maturation (Bedford 1975) affecting motility (Gaddum 1968) and the fertilizing ability of spermatozoa (Bedford et al 1973) may also be sequelae of inflammation Inflammation and infection are often mistakenly considered to be interchangeable terms Infections by microorganisms are just one among several causes of inflammation (Woolf 1977) Diagnostic and therapeutic criteria for the management of the inflammatory state of male accessory genital organs are the subjects of this chapter

Inflammation and Infection

Zusammenfassung

Der antispermatogenetische Effekt von Aspirin und dessen Praevention durch Prostaglandin E2



In einer experimentellen Arbeit an mannlichen Albino-Ratten wurde der Einflus von Aspirin auf die Spermatogenese untersucht; daneben wurde Prostaglandin E2 als mogliche Schutzsubstanz gepruft. Aspirin wurde intraperitoneal verabfolgt (5 mg/100 g Korpergewicht/Tag); Prostaglandin wurde subcutan (60 /μg/100 g Korpergewicht/zweimal taglich) gegeben.



Die Application von Aspirin verursachte einen Ruckgang der Leydigzellfunktion, Veranderungen in der Morphologie der Sertolizelle und einen allmahlichen Abfall der Spermatidenzahl. Prostaglandin E2 war in der Lage, den Einflus des Aspirins auf die Sertoli-Zell-Morphologie und die Spermatidendegeneration ohne signifikante Besse-rung der Leydigzellfunktion zu verhindern. Auf der Grundlage dieser Ergebnisse wird eine mogliche Beziehung zwischen dem Prostaglandin und der Spermatogenese des Hodens diskutiert.

Antispermatogenic Effect of Aspirin and its Prevention by Prostaglandin E2

Quantitative evaluation of spermatogenesis at stage VII of the cycle of the seminiferous epithelium and radioimmunoassay of plasma testosterone were performed in adult Wistar rats after intraventricular injection of 5,6-dihydroxytryptamine (5,6-DHT). The rats were killed 2, 10 and 21 days after injection. Brain 5-hydroxytryptamine (5-HT) and plasma testosterone levels were found to be significantly lower in all rats treated with 5,6-DHT. A significant reduction in step 7 spermatid count was also observed after 10 and 21 days. Supplementation with human chorionic gonadotrophin for 21 days in rats injected with 5,6-DHT partially prevented the step 7 spermatid degeneration and increased testosterone levels without producing any effect on brain concentrations of 5-HT. These results suggest that changes in testicular steroidogenesis and spermatogenesis are secondary to pituitary gonadotrophin release which, in turn, is under the influence of brain 5-HT neurones.

Effect of intraventricular injection of 5,6-dihydroxytryptamine on spermatogenesis and plasma testosterone levels in the rat

Zusammenfassung

Die Spermatogenese der Ratte: Effekt der L-Tryptophanbelastung



Im vorliegenden Experiment wurde die Wirkung des erhohten zentralen 5-Hydroxy-Tryptophan-Spiegels (5-HT) auf die Steroidsynthese und Spermatogenese im Rattenhoden untersucht. L-Tryptophan, Vorlaufer der 5-HT-Synthese im Gehirn, wurde mannlichen Ratten uber einen kurzen (7 Tage) und einen langen Zeitraum (21 Tage) injiziert. Die kurzfristige Behandlung hatte keinen Effekt auf den Spermatogenesezyklus bis zum Stadium VII, wohingegen die langfristige Behandlung zu einer degenerativen Veranderung fuhrte (verringerte Zahl der Keimzellen). Bei beiden Behandlungsarten reduzierte sich die Aktivitat des Δ5-3β-HSD des Hodens, ohne das die NADH2-gekoppelte Diaphorase-aktivitat beeinflust wurde. Die histologische Untersuchung auf Leydigzellen brachte ebenfalls eine deutliche Verringerung nach beiden Behandlungsarten zutage. Bei der langfristigen Behandlung normalisierte sich durch Verabreichung von hCG die Spermatogenese, ebenso wie die Aktivitat der Δ5-3β-HSD und die Zahl der Leydigzellen im Vergleich zur Kontrollgruppe.



Die Hemmung der Spermatogenese und Steroidsynthese ist Ausdruck der verminderten Freisetzung von Hypophysaren Gonadotropinen unter dem Einflus der erhohten 5-HT-Synthese nach L-Tryptophanbelastung.

Spermatogenesis in rat: effect of L-tryptophan loading.

Loading of L-tryptophan for 7 and 21 days increased brain 5-hydroxytryptamine (5-HT) level which was associated with decreased plasma testosterone level. Human chorionic gonadotropin (HCG) administration in L-tryptophan treated rats for 21 days increased the plasma testosterone level in spite of increased brain 5-HT level. These results suggest that brain 5-HT exerts an inhibitory influence on testicular steroidogenesis by modulating the gonadotropin-releasing-factor (GnRH) release and thence pituitary gonadotropins.

Brain 5-hydroxytryptamine and plasma testosterone in L-tryptophan treated rats.

Zusammenfassung

Mogliche α-adrenerge Beteiligung bei nikotin-induzierter Veranderung der Spermatogenese der Ratte



Nikotin verursacht in einem Experiment an Ratten (die Dosis lag hoher als beim Menschen ublich) einen Abfall der primaren Spermatocyten und eine Retardierung der Entwicklung der Spermatocyten in Spermatiden. Dieser Effekt des Nikotins war moglicherweise zweitrangig fur die gesteigerte Aktivitat der adrenomedullaren Catecholamine, seitdem der antispermatogenetische Effekt des Nikotins durch Phentolamine, einen bekannten Blocker der Catecholamin-Aktion auf den α-Rezeptor-Wert, verhindert wurde.

N.M. Biswas

Papers

Antispermatogenic Effect of Aspirin and its Prevention by Prostaglandin E2

Effect of intraventricular injection of 5,6-dihydroxytryptamine on spermatogenesis and plasma testosterone levels in the rat

Spermatogenesis in rat: effect of L-tryptophan loading.

Brain 5-hydroxytryptamine and plasma testosterone in L-tryptophan treated rats.

Possible Alpha‐Adrenergic Involvement in Nicotine Induced Alteration of Spermatogenesis in Rat