Reproductive outcomes of neonatal exposure to betamethasone in male and female rats.

Betamethasone (BM) is the drug of choice for antenatal corticosteroid therapy for women at risk of preterm delivery because it induces fetal lung maturation and enhances survival after birth. However, our group reported evidence of fetal programming and impaired reproductive development and function in rats exposed during the critical window of genital system development. Therefore, we aimed to investigate the effects of BM on the sexual development of rats in the period that corresponds to antenatal corticosteroid therapy in humans. Male and female rats were exposed subcutaneously to BM at 0.1 µg/g of pups' body weight or to a NaCl 0.9% solution (control) on postnatal days 1-3. It was observed that neonatal exposure to BM decreased body weight and weight gain in male and female rats during treatment. The estrous cycle was deregulated and LH level was decreased in female rats. In male rats, the sperm concentration in the caput-corpus of the epididymis was decreased, whereas the sperm transit time and sperm concentration in the cauda of the epididymis were increased. Our results demonstrated that neonatal exposure to BM impaired body growth of male and female rats, deregulated the estrous cycle of female rats, and altered sperm quality of male rats. Therefore, BM exposure from postnatal days 1 to 3 corroborated results previously observed after prenatal exposure to this drug. Despite the recognized importance of human antenatal corticosteroid therapy, the findings of this study should encourage further studies in order to minimize possible adverse postnatal effects.

Lorcaserin Administration has Pro-Ejaculatory Effects in Rats via 5-HT2C Receptors Activation: A Putative Pharmacologic Strategy to Delayed Ejaculation?

BACKGROUND: Lorcaserin is an anti-obesity drug whose weight loss effect results from 5-hydroxytryptamin (5-HT)2C receptors activation. The 5-HT2C receptor was shown to participate in the physiological control of ejaculation, but no data addressing a putative effect of lorcaserin on ejaculation exist. AIM: To investigate the effects of lorcaserin in different in vitro and in vivo experimental models of ejaculation in rats. METHODS: Contractile responses to lorcaserin in rat seminal emission organs in vitro (prostatic and epididymal vas deferens, cauda epididymis, and seminal vesicles), analysis of male rat copulatory behavior, and electromyographic recording of bulbospongiosus muscle in anesthetized animals were studied. MAIN OUTCOME MEASURES: The main outcome measures included in vitro contraction of seminal emission organs and evaluation of the male rat copulatory behavior. The male rat sexual behavior in terms of copulation latency, ejaculation latency, mount and intromission frequency, and ejaculation frequency of sexually experienced adult male rats with a receptive female were also recorded. RESULTS: Lorcaserin (1.0 nM to 1.0 mM) had no significant effects on the in vitro contractility of seminal emission organs smooth muscle (cauda epididymis, vas deferens, and seminal vesicles). On the other hand, lorcaserin administration (0.3-1.0 mg/kg, intravenous) induced ejaculation in anesthetized rats, which was prevented by the 5-HT2C-selective antagonist SB 242084 (0.1 and 0.3 mg/kg, intravenous). Single-dose treatment of non-anesthetized male rats with lorcaserin (1.0, 4.0, or 10 mg/kg, per os) induced non-copulating ejaculations in sexually naïve rats. Lorcaserin also had pro-ejaculation effects by decreasing the ejaculation threshold of copulating rats by half. The pro-ejaculatory effects of lorcaserin were reversible as the ejaculation threshold of treated rats recovered after a 1-week washout period. CLINICAL IMPLICATIONS: Due to its reported clinical safety, repurposing lorcaserin for the treatment of delayed ejaculation may be suggested. STRENGTHS & LIMITATIONS: The pro-ejaculatory effect of lorcaserin administration and the role of 5-HT2C were demonstrated in different experimental models of ejaculation in rats. The lack of studies in putative experimental models of delayed ejaculation is a limitation of this study. CONCLUSION: Our results demonstrate that the clinically approved 5-HT2C agonist lorcaserin is a strong facilitator of ejaculation in rats. de Almeida Kiguti LR, Pacheco TL, Antunes E, et al. Lorcaserin Administration has Pro-Ejaculatory Effects in Rats via 5-HT2C Receptors Activation: A Putative Pharmacologic Strategy to Delayed Ejaculation? J Sex Med 2020;17:1060-1071.

Effects of isolated or combined exposure to sibutramine and rosuvastatin on reproductive parameters of adult male rats.

Many obese patients are exposed to hypolipidemic and serotonin-norepinephrine reuptake inhibitor (SNRI) drugs. Statins are one of the most marketed drugs in the world to treat dyslipidemia, while sibutramine, a SNRI drug, is prescribed in some countries to treat obesity and is detected as an additive in many adulterated weight loss supplements marketed worldwide. Previous studies reported adverse effects of isolated exposure to these drugs on male rat reproductive parameters. In the present work, we further investigated male reproductive toxicity of these drugs, administered in isolation or combination in adult rats for a longer period of treatment. Adult male rats (90 days) were treated (gavage) for 70 days with saline and dimethyl sulfoxide (control), sibutramine (10 mg/kg), rosuvastatin (5 mg/kg), or rosuvastatin combined with sibutramine. Sibutramine alone or with rosuvastatin, promoted a reduction in food intake and body weight gain, weight of the epididymis, ventral prostate and seminal vesicle; as well as decreased sperm reserves and transit time through the epididymis; androgen depletion; and increased index of cytoplasmic droplet. The rosuvastatin-treated group showed reduced frequency of ejaculation. Exposure to this drug alone or combined with sibutramine impaired epididymal morphology. Co-exposed rats had altered epididymal morphometry, and seminal vesicle and testis weights. The rats also showed decreased fertility after natural mating and a trend toward a delay in ejaculation, suggesting a small synergistic effect of these drugs. Given the greater reproductive efficiency of rodents, the results obtained in the present study raise concern regarding possible fertility impairment in men taking statins and SNRI drugs.

Reproductive outcomes in rat female offspring from male rats co-exposed to rosuvastatin and ascorbic acid during pre-puberty.

Dyslipidemias are occurring earlier in different countries due to the increase of obesity, bad eating habits, and sedentary lifestyle. Rosuvastatin reduces serum cholesterol; however, several studies associated statin exposure with male reproduction impairment. Ascorbic acid (AA) is an antioxidant substance that plays a protective role in the male reproductive system. Male rats were randomly divided into 6 experimental groups (n = 10), which received saline solution 0.9%, 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of AA or 3 or 10 mg/kg/day of rosuvastatin associated with 150 mg/day of AA from post-natal day (PND) 23 until PND 53. On PND 100, males were mated with non-treated female rats to obtain the female pups. The day of vaginal opening and the first estrus were assessed in the offspring. Two sets of females were euthanized on the first estrus after PND 42 and PND 75 to evaluate the histology of reproductive organs and hormone levels. A third set was used for sexual behavior and fertility test around PND 75. Female offspring from males exposed or co-exposed to the higher dose of statin exhibited a lower number of corpora lutea during puberty. On sexual maturity, the experimental group from males that were exposed to 3 mg displayed lower uterine luminal epithelium area. Paternal exposure to rosuvastatin at pre-puberty diminished uterine luminal epithelium in female offspring suggesting epigenetic changes were initiated by statin. Ascorbic acid co-administered to pre-pubertal males was able to ameliorate the reproductive damage in rat female offspring in adulthood.

Impact of intrauterine exposure to betamethasone on the testes and epididymides of prepubertal rats.

Therapy with betamethasone, a synthetic glucocorticoid, is used in cases of preterm birth risk, in order to promote fetal lung maturation, and decrease neonatal mortality and morbidity. However, late reproductive disorders related to the prenatal exposure to this compound have been reported by our Laboratory, in both male and female rats. Thus, the present study aimed to evaluate the impact of betamethasone on postnatal reproductive development, during pre-puberty, of male offspring exposed in utero to this synthetic glucocorticoid. For this purpose, pregnant Wistar rats were allocated into two groups: Control, treated with saline, and the group treated with betamethasone at 0.1 mg/kg/day. Control and betamethasone groups were treated with intramuscular injection on gestational days 12, 13, 18 and 19, critical days of prenatal reproductive development. The treatment is associated with reduced body and organ weights, disorders in initial reproductive parameters of pre-pubertal male offspring exposed in utero to betamethasone, such as reduction of anogenital distance, alterations in histomorphometric parameters and immunostaining pattern of androgen and estrogen receptors on testicles and epididymides. Our results suggest that prenatal exposure to betamethasone potentially causes reproductive reprogramming and impairs male postnatal reproductive development. This data raise concerns about the use of betamethasone for human antenatal therapy.

Vitamin C partially prevents reproductive damage in adult male rats exposed to rosuvastatin during prepuberty.

Pediatric obesity is closely associated with dyslipidemias and environmental factors, such as diet and lack of physical exercises, which may alter lipid profile in children. Rosuvastatin decreases serum total cholesterol and triglycerides concentrations. Vitamin C (ascorbic acid) plays an important role on sperm integrity and fertility. Juvenile male rats were distributed into six experimental groups that received saline solution 0.9%, 3 or 10 mg/kg/day of rosuvastatin, 150 mg/day of ascorbic acid, or 3 or 10 mg/kg/day of rosuvastatin co-administered with 150 mg/day of ascorbic acid from PND23 until PND53 and then the rats were maintained until sexual maturity. Rosuvastatin-exposed groups showed lower sperm quality, androgen depletion and germ cell death. Ascorbic acid was capable to prevent partially the reproductive adverse effects provoked by rosuvastatin. In conclusion, prepubertal exposure to rosuvastatin provokes long-term reproductive damages at sexual maturity and ascorbic acid supplementation at prepuberty may be a preventive mode against these reproductive adverse effects.

Betamethasone causes intergenerational reproductive impairment in male rats.

Prenatal betamethasone (BM) exposure in rats negatively impacts sperm quality and male fertility. Studies have shown that BM can cause multi-generational effects on the pituitary-adrenal-axis of rats. The objective of this study was to assess the reproductive development and fertility of male rats (F2) whose fathers (F1) were exposed to BM (0.1mg/kg) on gestational days 12, 13, 18 and 19. In F2 rats, there was a significant reduction in body weights of the BM-treated group at PND 1 as well as delayed onset of puberty, and decreases in FSH levels, Leydig cell volume, sperm number and motility, seminal vesicle contractility and ejaculated volume. Furthermore, increased serum LH levels, sperm DNA damage and abnormal morphology were observed, resulting in reduced fertility. In conclusion, prenatal BM-treatment leads to intergenerational long-term reproductive impairment in male rats, raising concern regarding the widespread use of BM in preterm births.