Liraglutide treatment effects on rat ovarian and uterine tissues

Liraglutide is a Glucagon-like peptide-1 (GLP-1) analogue used for the treatment of type II diabetes mellitus and obesity. The present study aimed at investigating the effect of Liraglutide in ovarian and uterine tissues in albino rats. 30 female rats were divided into 3 groups, 10 rats each. Group (I) served as control group, group (II) animals administrated therapeutic doses of liraglutide for 5 weeks and group (III) animals were injected with Liraglutide as the pervious group. Then they were left for 2 weeks after drug termination as a recovery period. The biochemical results showed a decrease in the female reproductive hormones profile, luteinizing hormone (LH), follicle stimulating hormone (FSH), estrogen (ER), progesterone (PR) and an increase in the level of testosterone (T). Liraglutide administration caused a significant decrease in the antioxidant markers, glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) and a significant increase in the activity of malondialdehyde (MDA). The histopathological examination revealed apoptosis of granulosa cells of different types of follicles with an increase in atretic and disorganized follicles. Vacuolar degenerative changes, and Atrophied muscle with sever inflammatory cell infiltrate in endometrium with congested, dilated blood vessels could be detected in uterine tissues. However, most of the deleterious effects of liraglutide decreased after drug discontinuation. In this study, we clarify the harmful effect of the liraglutide on ovarian and uterine tissues, thus potentially causing reproductive health malfunction and reducing the chances of pregnancy.     

Assessment of chronic administration of aloe vera gel on haematology, plasma biochemistry, lipid profiles and erythrocyte osmotic resistance in wistar rats

The study was designed to investigate the effects of chronic administration of Aloe vera gel extract on markers of hepatic damage, lipid profiles and erythrocyte osmotic fragility using the Wistar rats. Forty male Wistar rats divided into four groups of ten rats per group were used in the study. Group I which served as the control received 0.9% physiological saline while those in groups II, III and IV received Aloe vera gel (100, 250 and 500mg/kg), respectively, for four weeks. There was significant increase in the haemoglobin concentration while the PCV, RBC count, MCH and MCHC though showed some marginal increases but the increases were not significant in all the treated rats. No significant change was also observed in the erythrocyte osmotic fragility. However, there were significant reductions in plasma ALT, AST and ALP levels in animals that received the gel compared with the control while the plasma albumin and total protein values were higher than those of the control. All the animals that received the gel also showed significant reduction in plasma total cholesterol, triglycerides and LDL-cholesterol ratio compared with the control. In a similar manner, those animals that were administered with 500mg/kg gel had significantly higher HDL-cholesterol ratio than those of the control. This study showed that, chronic administration of Aloe vera gel extract had no significant effects on the haematological parameters of the rats and did not affect erythrocyte osmotic resistance. It however showed some cholesterol lowering action.keywords: Aloe vera, Haematology, Osmotic fragility, Plasma biochemistry.     

Effects of chronic D-Leu6, des-Gly10-gonadotropin releasing hormone ethylamide on male sex tissues

The chronic administration of superactive agonists of gonadotropin releasing hormone (GnRH-A) have been reported to have a direct inhibitory effect on the sex tissues of the male rat. In an attempt to confirm or refute this statement, adult male rats were either left intact or were castrated and then treated daily for 14 days with either testosterone (T), dihydrotestosterone (DHT) or sesame oil (vehicle). Half of the intact and castrate animals also received daily injections of 200 ng of the GnRH agonist, D-Leu6, des-Gly10-GnRH ethylamide for 14 days. Twenty-four hours after completing treatment, blood levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and T were measured by radioimmunoassay and the ventral prostate gland (VP), seminal vesicle (SV) and penis were weighed. After 2 weeks of GnRH-A treatment, the plasma T level was reduced from 2506 +/- 170 (pg/ml +/- SEM) in the intact, nontreated animals to 907 +/- 69 in the intact, GnRH-A-treated group, indicating that the dosage of GnRH-A used in this study had an inhibiting effect on T secretion. No differences were observed in the VP, SV and penile weights between the castrate, GnRH-A and the castrate, nontreated groups. When exogenous T or DHT was given for 14 days to these castrated animals, the concomitant administration of GnRH-A did not appear to have any effect on the plasma T levels or the sex accessory tissue weights. These data suggest that GnRH-A itself does not appear to have a direct inhibitory or stimulatory effect on the sex tissues of the adult male rat.     

24-Hour Changes in Circulating Prolactin,Follicle-Stimulating Hormone,Luteinizing Hormone,and Testosterone in Young Male Rats Subjected to Calorie Restriction

This work analyzes the effect of calorie restriction on the 24 h variation of pituitary-testicular function in young male Wistar rats by measuring the circulating levels of prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Control animals were provided an equilibrium calorie diet and the experimental animals a calorie-restriction diet equivalent to 66% of food restriction for four weeks starting on day 35 of life. Different groups of control and experimental rats were killed at 6 h intervals around the clock, beginning 1 h after light on (HALO). Compared to the control animals, the mean secretion of prolactin was augmented and that of LH and testosterone decreased in calorie-restricted rats, whereas FSH release remained unchanged. Significant changes in the 24 h secretory pattern of circulating prolactin, LH, and testosterone occurred in the calorie-restricted rats. These include the appearance of a second maximum of plasma prolactin at 21 HALO, blunting of the LH peak seen at 13 HALO, and phase-shift of the testosterone peak from 13 HALO in controls to 17 HALO in calorie-restricted rats. The significant positive correlation between individual LH and testosterone levels found in controls was no longer observed in calorie-restricted rats. Availability of nutrients presumably affects the mechanisms that modulate the circadian variation of the pituitary-gonadal axis in growing male rats.     

Effect of Filgrastim on adult male rats’ fertility and reproductive performance

Filgrastim is a recombinant protein used in treatment neutropenia caused by myelosuppressive medications for patients with non-myeloid cancer. However, its effect in male fertility is not clear. So, the current work aims to clarify the effect of Filgrastim on the reproductive state in Wistar rats. Eighteen (18) male Wistar rats were divided into three groups (6/each). Group (I) where the rats were injected with 0.5 ml/kg/day of distilled water and served as Control Group. The Group (II) animals received intraperitoneal injection of therapeutic dose of 30.83 mcg/kg/day of Filgrastim for one week. The Group (III) rats received the same dose by the same route of Filgrastim for two weeks. Sera of blood samples were processed for serum follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (TS). Semen analysis and resazurine reduction test (RRT) were performed. Assaying for malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) was done. The testes were retrieved for histopathological and immunohistochemical studies for caspase-3 detection. Our results revealed that filgrastim affects sperm morphology, significantly decreased the RRT and the reproductive hormones level, elevated the oxidative stress status and induced several histopathological changes in testes with an increased in immunoexpression of caspase-3 in testes tissues. The results of this work demonstrated that Filgrastim may had a deleterious effect on male fertility.     

Bisphenol A inhibits testicular functions and increases luteinizing hormone secretion in adult male rats

Effects of a xenobiotic estrogen, bisphenol A (BPA), on reproductive functions were investigated using adult male rats. BPA was dissolved into sesame oil and injected s.c. every day (1 mg/rat) for 14 days. Animals were killed by decapitation after the final administration of BPA, and the trunk blood, pituitary, and testes were collected. Plasma concentrations of prolactin were dramatically increased and pituitary contents of prolactin were slightly increased in the BPA group compared to the control group. Plasma concentrations of testosterone were decreased and plasma concentrations of LH were increased in BPA-treated rats compared to control rats. Testicular contents of inhibin were decreased in BPA-treated rats compared to control rats, although plasma concentrations of inhibin were not changed after administration of BPA. The testicular response to hCG for progesterone and testosterone release was decreased in BPA-treated rats. Administration of BPA did not change the pituitary response to luteinizing hormone-releasing hormone (LH-RH) in castrated male rats treated with testosterone. Male sexual behavior also was not changed as a result of BPA treatment. These results suggest that BPA directly inhibits testicular functions and the increased level of plasma LH is probably due to a reduction in the negative feedback regulation by testosterone. The testis is probably a more sensitive site for BPA action than the hypothalamus-pituitary axis.     

Effect of sex hormones on plasma T-kininogen in the rat

The influence of sex hormones on rat plasma T-kininogen concentration was examined. The level of T-kininogen in the post-pubertal female rat is about 3-times that of the male animal. Female rats castrated as adults or 15 days after birth, had low T-kininogen concentrations, near those of male rats. In contrast, castration of mature or immature male animals induced no change in T-kininogen. Treatment of castrated female or male rats with 17 alpha-ethinylestradiol significantly increased the T-kininogen level, whereas administration of testosterone or progesterone had no effect. The influence of estrogen was specific for T-kininogen, since plasma HMW kininogen concentration was the same in male and female rats and was not affected by castration or sex hormone treatment. T-kininogen concentration was not significantly changed in pregnant rat between the 12th and the 20th day of pregnancy, but increased after parturition. It was high in the newborn rat at birth and then decreased similarly over the next 3 weeks in males and females. It continued to decrease in the males, reaching the level of the adult rat, but it increased in the female from 3-4 weeks of age and reached the adult level at about 6-8 weeks. These data indicate that natural estrogens have a physiological influence on the plasma level of T-kininogen in female rats whereas testosterone had no effect on either male or castrated female rats. HMW kininogen is not physiologically dependent on sex hormones.     

24-hour changes in circulating prolactin, follicle-stimulating hormone, luteinizing hormone, and testosterone in young male rats subjected to calorie restriction

This work analyzes the effect of calorie restriction on the 24 h variation of pituitary-testicular function in young male Wistar rats by measuring the circulating levels of prolactin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Control animals were provided an equilibrium calorie diet and the experimental animals a calorie-restriction diet equivalent to 66% of food restriction for four weeks starting on day 35 of life. Different groups of control and experimental rats were killed at 6 h intervals around the clock, beginning 1 h after light on (HALO). Compared to the control animals, the mean secretion of prolactin was augmented and that of LH and testosterone decreased in calorie-restricted rats, whereas FSH release remained unchanged. Significant changes in the 24 h secretory pattern of circulating prolactin, LH, and testosterone occurred in the calorie-restricted rats. These include the appearance of a second maximum of plasma prolactin at 21 HALO, blunting of the LH peak seen at 13 HALO, and phase-shift of the testosterone peak from 13 HALO in controls to 17 HALO in calorie-restricted rats. The significant positive correlation between individual LH and testosterone levels found in controls was no longer observed in calorie-restricted rats. Availability of nutrients presumably affects the mechanisms that modulate the circadian variation of the pituitary-gonadal axis in growing male rats.     

Androgen dependent brain differentiation and life span.

Intact females without neonatal hormone treatment served as control animals. A second group of female rats received 1.25 mg testosterone propionate subcutaneously on the first day of life causing in these genetic females a male-type brain differentiation. Male rats orchidectomized on the 75th day of life served as male "control" animals, since there was no lack of androgen during the neonatal phase of brain organization. A fourth treatment group consisted of males which had been orchidectomized on the first day of life representing males with female-type differentiated brains. The experimental animals belonging to the Sprague-Dawley-derived strain of our laboratory were kept under standard conditions for food, illumination and temperature.     

The influence of portacaval anastomosis on gonadal and anterior pituitary hormones in a rat model standardized for gender, food intake, and time after surgery

Portacaval anastomosis causes delayed growth, decreased testes and liver weights, and elevated estradiol serum levels in male rats compared with sham-operated controls. Female rats treated with portacaval anastomosis grow at a normal rate despite changes in liver weight and estradiol levels similar to those observed in the male rats. This study examined the pituitary gonadal axis in both genders in this animal model. The rats receiving portacaval anastomosis were compared with both pair-fed and sham-operated control groups. Portacaval anastomosis decreased serum testosterone and increased estradiol in the male animals, while both testosterone and estradiol were increased in the females compared with gender-matched pair-fed and sham controls. Because pair feeding lowers male testosterone to a lesser extent, impaired nutrition may partially account for the decrease in the males treated with portacaval anastomosis. The ratio of estradiol to testosterone increased following anastomosis in male rats, but it was decreased in similarly treated females. Portacaval and anastomosis decreased luteinizing hormone without changing follicle-stimulating hormone in both male and female rats compared with sham-operated controls. Growth hormone was significantly decreased in male portacaval-treated rats compared with sham- and pair-fed animals. Increased insulin levels were found in both male and female pair-fed and portacaval anastomosis-treated animals. These data suggest that following portacaval anastomosis in rats, growth, serum testosterone, estradiol to testosterone ratios, and growth hormone are altered in a gender-specific manner with gender-independent changes in insulin and luteinizing hormone levels. These gender-specific effects may protect the portacaval anastomosis-treated female rat from growth retardation.     

Alteration in the normal pattern of serum testosterone and 5α-androstane-3α,17β-diol in the immature male rat following chronic treatment with luteinizing hormone releasing hormone or luteinizing hormone

A major component of sexual maturation in the male rat is a progressive decline in serum concentrations of 5α-androstane-3α,17β-diol (3α-diol) and a concomitant increase in testicular testosterone biosynthesis and secretion. Chronic administration of synthetic luteinizing hormone releasing hormone (LHRH) or luteinizing hormone (LH)/human chorionic gonadotropin (hCG) to immature male rats has been shown to result in a delay in sexual maturation as evidenced by decreased sex accessory gland weights and altered testicular testosterone production. We have examined the postulate that such treatments may either reverse or retard the normal developmental pattern of serum testosterone and 3α-diol concentrations. Chronic $\text{in vivo}$ treatment of 28 day old immature male rats for 2 weeks with daily injections of either 0.5 μg of LHRH, 1.0 μg of LHRH, or 30 μg of LH was found to result in significant reductions in weights of the seminal vesicles and ventral prostate glands and diminutions in serum testosterone concentrations. Serum content of 3α-diol was either unchanged or slightly elevated in the LHRH treated animals and increased significantly in the LH treated animals. These data suggest that either a reversal of or retardation in the normal developmental pattern of serum testosterone and 3α-diol content has been achieved in the immature male rat by chronic LHRH or LH treatment.     

Effects of Exogenous Gonadal Steroids on Leptin Homeostasis in Rats

WU-PENG, SHARON, MICHAEL ROSENBAUM, MARGERY NICOLSON, STREAMSON C. CHUA, AND RUDOLPH L. LEIBEL. Effects of exogenous gonadal steroids on leptin homeostasis in rats. Obes Res. Background: In humans, circulating concentrations of the hormone leptin, normalized to body fat mass, are significantly higher in females compared to males. This experiment was designed to determine whether the administration of exogenous androgen or estrogen would significantly alter the relationship between plasma leptin and fat mass in rats. Methods: In the first experiment, plasma leptin and retro-peritoneal and parametrial (female)/epididymal (male) adipose tissue expression of leptin mRNA were measured in five male and five female 9. 5-week-old Sprague-Dawley rats. In a second experiment, gonadectomized 10. 5-week-old female Sprague-Dawley rats received 1 or 2 weeks of daily intraperitoneal injections (in oil) of 750 mg testosterone propionate, 2. 5 μg of estradiol benzoate or vehicle. At 0, 1, and 2 weeks, plasma concentrations of leptin, fat pad weight of parametrial and retroperitoneal fat pads, and leptin mRNA expression by Northern blot in retroperitoneal fat pads were determined. Daily weight and food intake of animals were monitored throughout the study. Results: Circulating leptin concentrations per unit of fat pad mass and leptin mRNA expression normalized to actin mRNA were higher in gonadally intact female compared to male rats. Compared to placebo, estrogen administration decreased food intake and body weight, but had no significant effect on leptin mRNA expression or on circulating leptin concentration. Testosterone administration increased body weight and decreased expression of leptin mRNA (only after 2 weeks), but did not change food intake or circulating leptin concentration. Conclusions: Administration of estrogen did not affect either leptin expression or the circulating concentration of leptin. Administration of androgen decreased expression of leptin mRNA. However, even after 2 weeks of testosterone administration to gonadectomized females, plasma leptin concentration, corrected for fat pad weight, was higher in gonadectomized females than in intact males, Thus, sex steroid-associated changes in plasma leptin concentration and leptin mRNA expression are not sufficient to explain the observed sexual dimorphism in plasma leptin concentrations in rats.     

Delay in the age of balano-preputial skinfold cleavage and alterations in serum profiles of testosterone, 5 alpha-androstane-3 alpha,17 beta-diol, and gonadotropins in adult rats treated during puberty with luteinizing hormone releasing hormone

Previous work has shown that chronic treatment of intact, immature male rats with luteinizing hormone releasing hormone (LHRH) decreases sex accessory gland weights and results in retardation of the normal developmental increase in the ratio of serum testosterone (T)/5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-Diol) via an apparent enhancement of testicular 5 alpha-reductase or 3 alpha-hydroxysteroid oxidoreductase activities. In the present work, androgen dependent balano-preputial skinfold cleavage was significantly delayed by approximately one week in intact, immature male rats which were treated daily for two weeks with either 1.0 micrograms, 2.5 micrograms or 5.0 micrograms of LHRH during a discrete phase of pubertal development (28-41 days of age). In intact, adult (62 day old) animals which received LHRH treatments during pubertal development, serum T concentrations and sex accessory gland weights were reduced compared to control animal values. Serum 3 alpha-Diol content in the adult rats was either unaltered or increased significantly depending on the LHRH dosage employed during sexual development. Serum luteinizing hormone concentrations were not different between control and LHRH-pretreated adult rats whereas the highest dosage of LHRH employed (5.0 micrograms) during puberty resulted in a significant elevation of adult serum follicle stimulating hormone levels. It is suggested that chronic LHRH treatment of the male rat during puberty results in a perturbation in testicular androgen biosynthetic activities and an impairment of pituitary-testicular hormone feedback mechanisms which persist at least through early adulthood.     

Reduced ability of naloxone to stimulate LH and testosterone release in aging male rats; possible relation to increase in hypothalamic met5-enkephalin

Blood luteinizing hormone (LH) and testosterone levels are lower in old than in young male rats. The specific opiate antagonist, naloxone, previously shown to increase serum LH in mature male rats, exhibited relatively little ability to raise serum LH and testosterone levels in old (18–20 mo) as compared to young (4–5 mo) male rats. The brain opiate, met⁵-enkephalin, which depresses LH, was found to be significantly higher in the hypothalamus of old than of young male rats. These observations suggest that hypothalamic opiates may be partially responsible for the lower serum LH and testosterone levels in old male rats, and for reduced release of these hormones in response to naloxone administration.     

Reproductive toxicologic evaluations of Bulbine natalensis Baker stem extract in albino rats

The effects of oral administration of aqueous extract of Bulbine natalensis Baker stem at daily doses of 25, 50, and 100 mg/kg body weight on the reproductive function of Wistar rats were evaluated. The indices of mating and fertility success as well as quantal frequency increased after 7 days of treatment in all the dose groups except the 100 mg/kg body weight group. The number of litters was not statistically different (P > 0.05) from the control. Whereas the absolute weights of the epididymis, seminal vesicle, and prostate were not affected, that of the testes was significantly increased. The epididymal sperm count, motility, morphology, and viscosity were not different from the control after 7 days of treatment. The male rat serum testosterone, progesterone, luteinizing hormone, and follicle-stimulating hormone significantly increased in the 25 and 50 mg/kg body weight groups, whereas the estradiol concentration decreased significantly at all the doses. The extract dose of 100 mg/kg body weight decreased the serum testosterone and progesterone levels in male rats. The prolactin concentration was not affected by all the doses. All the indices of reproduction, maternal, embryo/fetotoxic, teratogenic, and reproductive hormones in the female rats were not statistically different from that of their control except the resorption index, which increased at the dose of 100 mg/kg body weight of the extract. Histologic examination of the cross section of rat testes that received the extract at all the doses investigated revealed well-preserved seminiferous tubules with normal amount of stroma, normal population of spermatogenic and supporting cells, as well as normal spermatocytes within the lumen. The results revealed that the aqueous extract of Bulbine natalensis stem at doses of 25 and 50 mg/kg body weight enhanced the success rate of mating and fertility due to increased libido as well as the levels of reproductive hormones in male rats. The absence of alterations in the reproductive parameters of female rats at doses of 25 and 50 mg/kg body weight of Bulbine natalensis stem extract suggest that the extract is “safe” for use at these doses by females during the organogenic period of pregnancy, whereas the extract dose of 100 mg/kg body weight portends a negative effect on some reproductive functions of male and female rats.     

Influence of 50 Hz magnetic field on sex hormones and other fertility parameters of adult male rats

The effects of an extremely low frequency (ELF) magnetic field on the sex hormones and other fertility parameters of adult male Sprague-Dawley rats were investigated. Adult male rats were exposed to a 50 Hz sinusoidal magnetic field at approximately 25 microT (rms) for 18 consecutive weeks. There were no significant effects on the absolute body weight and the weight of the testes of the exposed rats. However, the weights of seminal vesicles and preputial glands were significantly reduced in the exposed male rats. Similarly, a significant reduction in sperm count was observed in the exposed group. Furthermore, there were no significant effects on the serum levels of male follicle stimulating hormone (FSH) during the 18 weeks of exposure period. On the other hand, there was a significant increase in the serum levels of male luteinizing hormone (LH) after 18 weeks of exposure (P < .005), while testosterone levels were significantly decreased only after 6 and 12 weeks of the exposure period. These results suggest that long term exposure to ELF could have adverse effects on mammalian fertility and reproduction.     

五味子对实验性水上漂浮及高强度运动大鼠垂体-性腺轴的影响

目的研究五味子对实验性水上漂浮及高强度运动大鼠垂体-性腺轴的影响。方法 34只SD大鼠随机分为非应激对照组（A组,n=10）、应激对照组（B组,n=12）和五味子干预组（C组,n=12）。A组不接受任何刺激,在生理盐水灌胃1周后进行取样。B组和C组进行为期10 d的递增负荷跑台训练,分别用生理盐水和五味子灌胃1周后,行3 h水上漂浮及3 h跑台高强度运动,结束即刻取血,测定血清皮质酮（CORT）、睾酮（T）、黄体生成素（LH）;随机取一侧睾丸,HE染色观察组织病理结构;电子显微镜下观察超微结构。结果 （1）B组大鼠与A组相比,睾酮水平显著下降;C组大鼠与B组相比,睾酮水平无明显变化,皮质酮水平显著降低;黄体生成素在3组之间均无显著变化。（2）HE染色示3组大鼠睾丸组织病理无明显变化。（3）电子显微镜观察发现,B组大鼠睾丸Leydig细胞线粒体肿胀,电子密度增高;C组大鼠睾丸Leydig细胞线粒体结构趋向于正常,可见分泌颗粒。结论五味子对实验性水上漂浮及高强度运动大鼠睾酮水平无明显作用,对睾丸超微结构有一定保护作用。     

Serum concentrations of reproductive hormones after administration of various anesthetics to immature and young adult male rats

Immature and young adult male rats were either castrated or unoperated. One of seven anesthetic agents (Rompun, Bio-Tal, Thiopental, pentobarbital, ketamine, halothane, or ether) was administered. When the animals were clearly anesthetized, they were decapitated. Control rats were decapitated without anesthesia. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, testosterone, and androstenedione were determined by radioimmunoassay. None of the anesthetics was clearly suitable for study of all these hormones. Most would be suitable for acute LH studies. Ketamine and halothane appeared inappropriate for FSH studies in immature rats. Pentobarbital, Rompun, and ether caused increases in serum prolactin. Most of the agents appeared to cause a reduction in serum testosterone in intact rats but an increase in castrated animals, suggesting an inhibition of testicular androgen secretion and a stimulation of adrenal androgen secretion.     

慢性镉负荷雄性大鼠的睾丸及生殖内分泌功能活动

选择健康SD雄性成年大鼠60只,随机分成对照组（C组）、镉负荷中剂量组（M组）和镉负荷高剂量组（H组）,每天分别饲喂含镉0,5,10mg/kg的大鼠全价饲料,连续6周,研究了镉负荷对大鼠睾丸及生殖内分泌功能活动的影响。结果显示：在整个实验期内,M和H组大鼠睾丸组织中的镉含量极明显上升,锌含量销有下降,与对照组差异不显著;血浆镉、锌含量虽分别表现稍有升高和下降,但与对照组比较无明显差异;H组睾丸精子头计数和每日精子生成量在镉负荷第3周极显著下降,第6周时,M和H组均极明显低于对照组;在整个实验期内,H组大鼠ALP活明显低于C组;LDH－X活性在M和H组大鼠均极明显低于C组;M和H组血浆T水平下降,均低于或显著低于C组;3组间的FSH和LH水平无明显差异。结果提示：慢性镉负荷在睾丸组织中逐步蓄积可引起睾丸一些酶活性改变、精子生成减少及内分泌功能活动低下。     

A new class of pentapeptide KISS1 receptor agonists with hypothalamic–pituitary–gonadal axis activation

The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH₂ (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.