Acceleration of Sperm Transit Time and Reduction of Sperm Reserves in the Epididymis of Rats Exposed to Sibutramine

Abstract

Sibutramine is a drug globally used for the treatment of obesity. The aim of this study was to investigate male reproductive disorders caused by sibutramine in adult rats. Wistar rats were treated for 28 consecutive days (gavage) with 10 mg/kg of sibutramine. Control animals received only vehicle (dimethylsulfoxide and saline). The rats were sacrificed for evaluation of body and reproductive organ weights, sperm parameters, hormone levels (luteinizing hormone, follicle-stimulating hormone, and testosterone), testicular and epididymal histopathology, sexual behavior, fertility and in vitro contractility of the epididymal duct. Sibutramine decreased (P , .05) weights of the epididymis and ventral prostate, but not of other reproductive organs. The sperm number and transit time in the epididymal cauda were decreased (P , .001), but the daily sperm production was not altered. Moreover, morphology and sperm motility, histopathology of the testes and epididymis, sexual behavior, fertility, and serum hormone levels were not altered by the treatment. Sibutramine increased the potency of norepinephrine and, per se, increased the mechanical activity of the epididymal duct in vitro. Thus, although sibutramine in these experimental conditions did not interfere with the reproductive process of rats, it provoked acceleration of the sperm transit time and a decrease in the sperm reserves in the epididymal cauda. This alteration is probably related to the sympathomimetic effect of this drug, as shown by the in vitro assays. In humans, use of this drug might present a threat for male fertility because sperm reserves in men are naturally lower than those in rats.

hERG channel function: beyond long QT

“…In this context, the channel appears to regulate extracellular calcium influx, as the activity is not sensitive to thapsigargin treatment 70 . The movement of rat sperm in the epididymal tract is similarly accelerated by the potassium channel blocker sibutramine, although whether this is due to the activity of the rat ERG channel remains unclear 71 .…”

K+ and Cl− Channels and Transporters in Sperm Function

“…The function of various K + channels has been implicated at least during the transport and maturation processes. Transport of sperm through the epididymis is achieved by hydrostatic pressure and by smooth muscle contractions of the epididymis (Bellentani et al, 2011). It has been reported that voltage-gated K + channels play a role in the control of smooth muscle contraction.…”

Epididymal contraction and sperm parameters are affected by clonidine

“…The putative relationship between the treatment with crescent doses with clonidine and hormonal or metabolic alterations is uncertain and needs further investigation. However, the reduction in epididymis weight may be related in part to the decrease in the in the sperm reserves induced by sperm transit time acceleration (Fernandez et al, 2008;Bellentani et al, 2011;Borges et al, 2013). Furthermore, it has been described that the a 2 -adrenoceptors mediate anti-lipolytic effects in fat cells, regulating the lipolysis induced by the activation of b-adrenoceptors (Lafontan & Berlan, 1995).…”

“…The increase in the frequency or amplitude of spontaneous contraction induced by hormones or drugs can diminish the sperm transit time and, consequently, the sperm reserves, promoting fertility impairment (Din-Udom et al, 1985;Chaturapanich et al, 1999;Bellentani et al, 2011). Therefore, the decrease in the sperm transit time (accelerated transit) and sperm reserves (as shown in Table 4) can be related to the increase in the frequency and amplitude of spontaneous contractions of caput/corpus and cauda epididymis (showed in this study) induced by the in vivo treatment with crescent doses of clonidine.…”