Urinary metabolites of the new progestagen STS 557 (17α-cyanomethyl-17-hydroxy-4,9-estradien-3-one) in the dog and rat

Urinary metabolites of the new progestagen STS 557 (17α-cyanomethyl-17-hydroxy-4,9-estradien-3-one) were isolated and characterized following oral administration of the 14α, 15α-tritium labelled compound to dogs and rats. 17α-Cyanomethyl-11β, 17-dihydroxy-4, 9-estradien-3-one (11β-OH-STS 557) and 17α-cyanomethyl-1,3,5(10),9(11) -estratetraene-3, 17-diol were identified by comparison with synthesized reference compounds. Mass spectra data indicate the following other pathways of STS 557 biotransformation: Hydroxylation in other positions than 11; hydrogenation; hydroxylation + hydrogenation; alteration of the 17α-side chain.     

Effect of 17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one on reproductive organs of the male laboratory mouse

The effect of subcutaneous administration (10, 15 and 20 mg/kg body weight/day, for 21 days; and 20 mg/kg body weight/day, for 28 days) of 17 alpha-cyanomethyl-17 beta-hydroxy- estra-4, 9-dien-3-one (STS 557) on the male reproductive organs of the Parkes strain mouse was investigated. The effect of the treatment on the testis was not uniform; both regressed and normal seminiferous tubules were observed in the same section of the organ. Furthermore, the histological changes observed in the seminiferous tubules in testes of STS 557--treated mice were not different in different dosage groups. In general, in moderately affected seminiferous tubules, the germinal epithelium was thin and consisted of Sertoli cells, spermatogonia, spermatocytes and spermatids; such tubules showed presence of many vacuoles in the epithelium. In severe cases, the tubules had collapsed and were lined by mainly Sertoli cells, spermatogonia and spermatocytes. The treatment also caused marked depression in motility and concentration of spermatozoa in cauda epididymidis, weight of accessory sex glands and in the levels of sialic acid and fructose in the epididymis and seminal vesicle, respectively. By 56 days of drug withdrawal, the alterations induced in the reproductive organs returned to control levels, suggesting that STS 557 treatment induces reversible alterations in the male reproductive organs of Parkes strain mouse.     

Testicular weight, tubular diameter and number of Sertoli cells in rats are decreased after early prepubertal administration of an LHRH-antagonist; the quality of spermatozoa is not impaired

To suppress gonadotropin secretion during the sensitive period in development of the testes, immature male rats were treated with an antagonist of luteinizing hormone-releasing hormone (LHRH; ORG. 30276) from postnatal days 6-15. Previously, it has been demonstrated that this treatment results in delayed pubertal development, decreased testicular weight, impaired fertility and adult sexual behavior. In the present experiments it was investigated whether the decreased testicular weight was correlated with morphological changes in the testis. Also, by using an artificial insemination technique, the biological activity of spermatozoa of adult male rats, treated during early prepuberty with the LHRH antagonist (LHRH-A), was tested. The present results demonstrated a decrease in the diameter of the testicular tubuli of LHRH-A-treated rats. The number of Sertoli cells per tubular cross-section was also smaller. But qualitatively no differences could be observed in the testis. All stages of maturation of the seminiferous epithelium were equally frequently represented in LHRH-A-treated males compared with controls. Artificial insemination using spermatozoa obtained from the epididymis of LHRH-A-treated rats, resulted in a pregnancy rate of 100%, similar to the control rate. From the present data, we conclude that the infertility in adult male rats, treated with an antagonist to LHRH during prepubertal life, does not result from malfunction in the maturational processes in the germinal cells and the testes as a whole, despite the observation of changes in the testicular morphology. The infertility of LHRH-A-treated male rats can be explained by the observed impairment of sexual behavior. We suggest, that a central action of the antagonist of LHRH when administered to immature male rats may lead to permanent changes in the development of sexual behavior.     

Time Course for Onset and Recovery from Effects of a Novel Male Reproductive Toxicant: Implications for Apical Preclinical Study Designs

In the pharmaceutic ICH S5(R2) guidelines for reproductive toxicity testing, a premating dose duration of 14 days is considered sufficient for assessment of male fertility for compounds that are not testicular toxicants. A novel α7 subtype of nicotinic acetylcholine receptor (α7nAChR) agonist, originally intended for treatment of Alzheimer's disease, did not cause changes in sperm counts, motility, or testicular histopathology in rat toxicity studies of up to 6 months duration. However, profound decrements in male fertility (reduced pregnancy rates and litter sizes) occurred after 11 weeks of dosing in male rats. In two time‐course investigations, dosed male rats were paired with undosed females after 5, 14, and 28 daily doses and again after 2 and 4 weeks off‐dose. Effects on male fertility were undetectable after 5 days. After 14 days, there was no effect on pregnancy rate, but preimplantation losses were increased. Effects on both pregnancy rates and preimplantation losses were clearly detectable after 28 days, but were of lesser magnitude than after 11 weeks of dosing. Fertility recovered rapidly after dose cessation. These studies illustrate the sensitivity of a long premating dose period at revealing hazard and determining the magnitude of effect on male fertility for compounds that are intended for chronic administration and do not affect testicular histopathology     

Nestorone: a progestin with a unique pharmacological profile

Nestorone(R) (Nestorone 16-methylene-17alpha-acetoxy-19-norpregn-4-ene-3,20-dione), formerly referred to as ST 1435, is a potent progestin when given parenterally via sustained release formulations. The pharmacological profile of Nestorone was compared with that of levonorgestrel and 3-keto-desogestrel by steroid receptor binding studies and by in vivo bioassays in rats and rabbits. 3-Keto-desogestrel showed the highest binding affinity to progesterone receptors (PR) followed by Nestorone, levonorgestrel, and progesterone. The binding affinity of Nestorone to androgen receptors (AR) was 500- to 600-fold less than that of testosterone. However, both levonorgestrel and 3-keto-desogestrel showed significant binding (40 to 70% of testosterone) to AR. None of the progestins bound to estrogen receptors (ER). The progestational activity of Nestorone, levonorgestrel, and progesterone was compared using McPhail index in immature rabbits and pregnancy maintenance and ovulation inhibition tests in rats after subcutaneous (s.c.) administration. In all three tests, Nestorone was the most potent progestin. The progestational activity of Nestorone was also compared after oral and s.c. administration in rabbits. The potency of Nestorone was over 100-fold higher upon s.c. administration than via the oral route. The androgenic activity of progestins, based on the stimulation of ventral prostate (androgenic target) and levator ani (anabolic target) growth in castrated immature rats, showed good correlation with their binding affinity to AR. Nestorone showed no androgenic or anabolic activity. Nestorone did not bind to sex hormone binding globulin (SHBG), whereas both levonorgestrel and 3-keto-desogestrel showed significant binding to SHBG. The estrogenic/antiestrogenic activity of Nestorone was investigated in immature ovariectomized rats. In contrast to estradiol and levonorgestrel, Nestorone showed no uterotropic activity in ovariectomized rats. Despite significant binding to glucocorticoid receptors (GR), Nestorone showed no glucocorticoid activity in vivo. It is concluded that a strong progestational activity, combined with lack of androgenic, estrogenic, and glucocorticoid-like activities, confer special advantages to Nestorone for use in contraception and hormone replacement therapy.     

Induction of the self-priming effect of luteinizing hormone releasing hormone during the sexual maturation of the male rat

Pubertal and young adult male rats release more luteinizing hormone (LH) in response to luteinizing hormone releasing hormone (LHRH) if pretreated with LHRH than if pretreated with saline. Immature male rats do not show this self-priming effect. In order to examine the role of acute changes in testicular steroids in this process, immature (29-30 days old) or pubertal (50-51 days old) male rats were castrated or sham operated under ketamine HCl anesthesia. Beginning immediately after completion of the surgery, they were given three priming injections of 10 ng LHRH/100 g body wt or saline at 30-min intervals. Thirty minutes after the third priming injection, a blood sample was obtained by cardiac puncture followed immediately by a challenge injection of 50 ng LHRH/100 g body wt given to both saline and LHRH primed groups. Ten minutes after the challenge injection a final blood sample was obtained by heart puncture. Serum was assayed for LH concentration by radioimmunoassay. Sham-operated pubertal rats showed a typical self-priming effect. Animals pretreated with LHRH released significantly (P less than 0.01) more LH in response to the challenge injection than did rats pretreated with saline. Acute castration also resulted in a significant (P less than 0.001) self-priming effect in pubertal rats. As anticipated, sham castrated immature males did not show a self-priming effect. Acutely castrated immature rats however, showed a significant (P less than 0.05) self-priming effect. These data provide support for the hypothesis that, prior to puberty, increases in testosterone during the priming process inhibit the expression of the self-priming effect.     

Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly known as dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Using a mouse model, we previously found that adult female mice exposed in utero to TCDD (F1 generation) as well as multiple subsequent generations (F2-F4) exhibited reduced fertility and an increased incidence of spontaneous preterm birth. Additional studies revealed that male F1 mice with a similar in utero/developmental TCDD exposure also exhibited diminished fertility and conferred an increased risk of preterm birth to their unexposed mating partners. Herein, we extend these previous observations, reporting that reduced fertility in male F1 mice is linked to testicular inflammation which coincides with apoptosis of developing spermatocytes, sub-fertility and an increased risk of preterm birth in their unexposed mating partners. Significantly, in the absence of additional toxicant exposure, testicular inflammation and reduced fertility persisted in F2 and F3 males and their control mating partners also frequently exhibited spontaneous preterm birth. Although a steady, global decline in male fertility has been noted over the last few decades, the reasons for these changes have not been firmly established. Likewise, the PTB rate in the U.S. and other countries has paralleled industrial development, suggesting a possible relationship between environmental toxicant exposure and adverse pregnancy outcomes. Most current clinical strategies to prevent preterm birth are focused solely on the mother and have yielded limited benefits. In contrast, our studies strongly suggest that the preconception testicular health of the father is a critical determinant of pregnancy outcomes in mice. Future clinical studies should examine the potential contribution of the male to gestation length in women and whether efforts to reduce the incidence of preterm birth should be initiated in both parents prior to pregnancy.     

Effect of estradiol benzoate on hormonal profile and steroidogenic organs of immature and adult male rats

The effects of estradiol benzoate (E2B) at a dose of 50 micrograms/day/rat for 15 days were investigated on ascorbate metabolism, steroidogenesis, protein, cholesterol levels of testis, adrenal and serum testosterone, LH and FSH profiles of rats. The data revealed that E2B manifested a direct effect on testicular and probably adrenal steroidogenesis. But serum gonadotrophin levels remained unchanged. The treatment also brought about a decline in ascorbate metabolism, activities of 3 beta and 17 beta hydroxysteroid dehydrogenases and alteration in protein level concomitant with the accumulation of cholesterol in both steroidogenic organs. Estrogen treatment was more effective in adult male rats than in the immature ones.     

Fertility and Developmental Toxicity Assessment in Rats and Rabbits with LY500307, a Selective Estrogen Receptor Beta (ERβ) Agonist

LY500307 is a selective estrogen receptor beta (ERβ) agonist that was developed for the treatment of benign prostatic hyperplasia. The in vitro functional selectivity of LY500307 for ERβ agonist activity is 32‐fold above the activity at the alpha receptor (ERα). LY500307 was evaluated in a series of male (M) and female (F) rat fertility and rat and rabbit embryo‐fetal development (EFD) studies, using 20 or 25 animals/group. LY500307 was administered daily by oral gavage starting 2 weeks (F) or 10 weeks (M) before mating, during cohabitation, until necropsy (M) or through gestation day (GD) 6 (F) in the fertility studies and from GD 6 to 17 (rats) or GD 7 to 19 (rabbits) in the EFD studies. Dosage levels of LY500307 ranged from 0.03 to 10 mg/kg/day for rats and from 1 to 25 mg/kg/day for rabbits. Fertility, estrous, maternal reproductive endpoints, conceptus viability, sperm parameters, organ weights, and histopathology were evaluated in the fertility studies. Maternal reproductive endpoints and fetal viability, weight, and morphology were evaluated in the EFD studies. Toxicokinetics were assessed in satellite animals. At 10 mg/kg/day in the male fertility study, findings included decreased body weight (BW); food consumption (FC); fertility, mating, and conception indices; sperm concentration; and reproductive tissue weight (associated with atrophic histologic changes). In the female fertility study, effects included decreased BW and FC at ≥0.3 mg/kg/day and persistent diestrus, delayed mating, and reduced fertility/conception indices at 3 mg/kg/day. In the rat EFD study, findings included decreased maternal BW and FC and increased incidences of adverse clinical signs, abortion, maternal mortality/moribundity, postimplantation loss, and fetal skeletal variations at 3 mg/kg/day. Effects in the rabbit EFD study were limited to decreases in maternal BW and FC at 25 mg/kg/day. In general, systemic maternal exposure increased proportionally with dosage in rats, but less than proportionally in rabbits. In conclusion, the no‐observed adverse effect levels following LY500307 administration were 1 mg/kg/day for male rat fertility, 0.3 mg/kg/day for female rat fertility and EFD, and 25 mg/kg/day for rabbit EFD. Adverse reproductive and developmental effects only occurred at or above parentally toxic dosage levels and were considered predominantly due to off‐target ERα effects.     

Regulation of testicular and Sertoli cell gamma-glutamyl transpeptidase by follicle-stimulating hormone

Hormonal deprivation achieved by hypophysectomy or gonadotropin-releasing hormone (GnRH)-antagonist treatment of immature rats resulted in markedly lower testicular gamma-glutamyl transpeptidase (GGT) activity than in the testes of age-matched controls. When begun 15 days after hypophysectomy, follicle-stimulating hormone (FSH) treatment significantly increased testicular GGT above that in testes from hypophysectomized controls in a time- and dose-dependent manner. In contrast, testosterone propionate had only a small effect. Testicular GGT was higher in adult hypophysectomized rats treated with FSH from the time of surgery than in untreated hypophysectomized rats; testosterone propionate treatment had no effect. GGT activity in Sertoli cells isolated from GnRH antagonist-treated or hypophysectomized immature rats was also lower than in cells from control rats. FSH treatment from the day of hypophysectomy resulted in Sertoli cell GGT values equivalent to those from intact controls. These data indicate that FSH regulates GGT activity in rat testis and Sertoli cells.     

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.     

Antigonadal activity of the neurohypophysial hormones: in vivo regulation of testicular function of hypophysectomized rats

The "antigonadal" potential of the neurohypophysial hormones, previously demonstrated in vitro, was evaluated in vivo using hypophysectomized male rats. This approach minimizes the likelihood that the in vivo "antigonadal" effect of the neurohypophysial hormones may be due to their ability to attenuate the release of pituitary gonadotropins. Given that the identity of the putative endogenous occupant of testicular pressor-selective neurohypophysial receptors remains uncertain, use was made of a substitute probe, arginine vasotocin (AVT), the utility of which has been demonstrated in vitro. Concurrent in vivo treatment of follicle-stimulating hormone (FSH; 5 micrograms/rat/day)-maintained immature hypophysectomized rats with increasing doses of AVT (0.25-25 microgram/rat/day) produced significant (P less than 0.05) dose-dependent inhibition of the testicular luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor binding capacity (but not affinity; Kd = 1.8 X 10(-10) M) from 8.8 +/- (standard error; SE) 0.4 ng/testis to a level (3.2 +/- 0.2 ng/testis) lower than that of controls (64% reduction). This AVT-induced decrease in the testicular LH/hCG receptor content of FSH-maintained immature hypophysectomized rats was associated with significant (P less than 0.05) decrements in the hCG- and N6, 2'-O-dibutyryladeosine cyclic 3',5'-monophosphate [( Bu]2cAMP)-stimulated accumulation of 3 alpha-hydroxy-5 alpha-androstan-17-one (androsterone; 52% and 42% inhibition, respectively), with virtual elimination (98% inhibition) of the forskolin-stimulated accumulation of extracellular cAMP by testicular incubates in vitro, as well as with profound suppression of spermatogenesis. Taken together, these observations indicate that the "antigonadal" effect of the neurohypophysial hormones previously demonstrated in vitro, can be fully reproduced in vivo, and that the "antigonadal" activity of the neurohypophysial hormones may be accounted for, in large part, by decreased testicular LH/hCG binding capacity, stimulable adenylate cyclase activity, and cAMP-supported androgen biosynthesis.     

二化螟雄蛾交配行为与精巢大小的关系

【目的】为了明确二化螟Chilo suppressalis雄蛾交配行为与精巢大小的关系,阐明信息素群集诱杀防治二化螟的有效性。【方法】本研究通过测定和比较不同日龄、交配状态以及性信息素诱捕的二化螟雄蛾精巢体积,建立精巢体积与雄蛾发育及交配状态的相关性。【结果】雄蛾日龄显著影响二化螟的交配,刚羽化(0日龄)雄蛾的交配率较低,1日龄雄蛾的交配率最高,之后随着日龄增加交配率逐渐降低。精巢体积与二化螟雄蛾日龄之间存在显著的负相关性。同一日龄交配的二化螟雄蛾的精巢体积显著大于未交配雄蛾;性诱捕器诱捕雄蛾的精巢体积显著大于未被性诱捕器诱捕雄蛾,与已交配雄蛾的精巢体积相似。交配之后,精巢的发育过程和未交配雄蛾相似。田间性信息素引诱二化螟雄蛾精巢体积小于0-1日龄未交配雄蛾,大于2-6日龄未交配雄蛾。【结论】本研究结果表明,二化螟雄蛾对雌蛾性信息素的反应与其精巢大小存在正相关性;性信息素引诱的二化螟雄蛾具有更强的性信息素反应能力,同时性信息素引诱的大部分雄蛾为未交配状态;交配过程并不影响二化螟雄蛾精巢体积,也不影响精巢发育。二化螟交配能力与精巢大小的关系在理论上解释了性信息素群集诱杀二化螟的防控有效性,并为其他蛾类昆虫的交配研究提供依据。     

Factors involved in the maintenance of luteal function in the pseudopregnant rat

Some data on a new antispermatogenic and antifertility compound, DL-6-(N-alpha-pipecolinomethyl)-5-hydroxy-indane maleate (PMHI) are presented. It was found that PMHI depressed testicular weight and interfered with spermatogenesis and fertility in the male rat. At equal doses, by weight, PMHI caused a greater reduction in testicular weight than WIN 18446, nitrofurazone, methallibure, and diethylstilbestrol, but lesser reductions in seminal vesicle and ventral prostate weights than were obtained with the 2 antigonadotropic compounds, methallibure and diethylstilbestrol. The data obtained in the experiments indicate that administration of PMHI causes sterility in male rats as a consequence of antispermatogenic activity. At low dosage levels (3 mg/kg), the action was reversible, but animals given 6.25 mg/kg/day or more remained sterile for 19 weeks following the treatment period. Doses of the compound which were effective in the male rat did not interfere with normal estrous cycles or fertility when administered to female rats.     

Testicular interleukin-6 response to systemic inflammation

Spermatogenesis is a highly controlled process of proliferation, meiosis, and differentiation. Systemic infection and chronic inflammation can impair testicular steroidogenesis and spermatogenesis. In this study, we examined the effect of systemic infection--intraperitoneal (i.p.) injection of lipopolysaccharide (LPS)--on the expression levels of IL-6 in the testis of sexually immature and adult mice. IL-6 levels in testicular homogenates of immature mice were significantly higher than in mature mice (both protein and RNA levels), before and after LPS injection. Injection of LPS (i.p.) into mature mice over 3 hours, significantly increased testicular IL-6 protein and mRNA levels (as demonstrated by ELISA and RT-PCR respectively) compared to the control group. Injection of LPS over 24 hours significantly increased IL-6 mRNA expression, but it did not significantly affect IL-6 protein levels in the homogenates. In contrast, stimulation of immature mice with LPS (2, 20 or 100 microg/mL) over 3 hours or LPS (2 or 20 microg/mL) over 24 hours, significantly increased testicular IL-6 (both protein and mRNA expression). The levels of testicular IL-6 (protein) in the homogenates were not significantly increased after stimulation with 100 microg/mL over 24 hours, but they were significantly increased at the mRNA level. Our results demonstrate, for the first time, the over-expression of IL-6 in testicular homogenates of mature and immature mice following systemic inflammation (i.p. injection of LPS). These results suggest the possibility of the involvement of systemic infection/inflammation, through the elevation of testicular IL-6, in testicular functions, which may affect male fertility. Also, high levels of IL-6 during pathological conditions, could play a role in protecting testicular tissue.     

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.     

Lupron depot prevention of antispermatogenic/antifertility activity of the indenopyridine, CDB-4022, in the rat.

The goals of this study were to determine the CDB-4022 dose-response relationship for induction of acute decreases in testicular weight and germ cell depopulation in rats; establish the threshold dose of CDB-4022 required to induce infertility; and investigate whether CDB-4022-induced testicular damage could be prevented by a GnRH agonist (Lupron Depot). Reduction of testis weight and germ cell depopulation were observed 7 days after a single oral dose of 1 mg CDB-4022/kg, whereas 0.5 mg/kg had no observable effect. These effects were maximal at 12.5 or 25 mg CDB-4022/kg. After a single oral dose of either 2.5 or 5 mg/kg, CDB-4022 induced infertility in five of five treated rats by Week 5, whereas only one of five males was rendered infertile at a dose of 1 mg/kg. Proven fertile male rats (6/group) were treated with vehicle, CDB-4022 alone (2.5 mg/kg on Day 0), CDB-4022 plus Lupron Depot (on Weeks -1, 2, 5, and 8), or Lupron Depot alone. Control males demonstrated normal fertility throughout a 32-wk cohabitation period. Five of six rats were rendered transiently infertile with Lupron Depot alone, but all recovered fertility. CDB-4022 treatment resulted in infertility in all six rats, and only one of six regained fertility. Combined treatment also caused infertility in all six rats, but four of six recovered fertility (P = 0.08 compared to CDB-4022 alone). Testicular weight was decreased in the three treatment groups compared to vehicle controls; testicular weights were ranked from highest to lowest as follows: vehicle > Lupron Depot > Lupron Depot + CDB-4022 > CDB-4022. The tubule differentiation index of Lupron Depot-treated rats (96 +/- 4%) was not different from vehicle-treated rats (100%). CDB-4022 treatment decreased the number of differentiating tubules (15 +/- 8%). Lupron Depot plus CDB-4022 treatment resulted in a greater number of differentiating tubules (53 +/- 12%) than CDB-4022 alone, but this was still lower than vehicle- or Lupron Depot-treated rats. These data indicate that 2.5 mg/kg of CDB-4022 was the oral threshold dose that caused testicular damage rendering the majority of adult male rats permanently infertile within the study interval; 12.5 mg/kg of CDB-4022 induced maximal testicular damage. Suppression of gonadotropins and/or testosterone production by treatment with Lupron Depot before and after CDB-4022 prevented the CDB-4022-induced irreversible testicular damage.     

Multiple mating of male and female codling moth (Lepidoptera: Tortricidae) in apple orchards treated with sex pheromone

Studies were conducted with codling moth, Cydia pomonella L., to evaluate the mating status of male and female moths in apple, Malus domestica (Borkhausen), orchards treated with and without sex pheromone dispensers. Laboratory studies first examined the effect of multiple mating of male and female moths on female fecundity and egg fertility. Females that had mated three times had a significantly higher fecundity than singly mated moths. Sequential mating by male moths had no effect on the fecundity of female moths or egg fertility. However, male moth age did impact female fecundity, with significantly fewer eggs laid after mating with virgin 1- versus 3-d-old males. The mean size of the first spermatophore transferred by males was significantly larger than all subsequent spermatophores. Classifying spermatophores based on size was used in field sampling to categorize the mating status of the female's partner. The proportion of mated females with small spermatophores (partner had previously mated) was significantly higher in treated versus untreated orchards. The proportion of female moths caught in traps baited with pear ester that were virgin was low (相似文献   

α‐Lipoic acid inhibits testicular and epididymal oxidative damage and improves fertility efficacy in arsenic‐intoxicated rats

The present study evaluates the protective effect of α‐lipoic acid (LA) against arsenic‐induced testicular and epididymal oxidative damage in rats. Arsenic caused significant reduction in the reproductive organ weights, serum testosterone levels, testicular daily sperm count, epididymal sperm count, sperm motility, sperm viability, and sperm membrane integrity. Significant reduction in the activity levels of superoxide dismutase, catalase, and glutathione levels with a concomitant increase in the lipid peroxidation and protein carbonyl content in the testis and the cauda epididymis of arsenic‐exposed rats. Arsenic intoxication also enhanced the testicular caspase‐3 mRNA levels, disorganization of testicular and cauda epididymal architecture as well as increased arsenic content in the testis and the cauda epididymis of rats. Arsenic exposure also deteriorated fertility ability in male rats over controls. Conversely, α‐LA negated the testicular and cauda epididymal oxidative stress and restored the male reproductive health in arsenic‐exposed rats.     

Suppression of testicular maturation and fertility following androgen administration to neonatal male rats

Administration of supraphysiologic doses of androgen to male rats within the first few neonatal days markedly suppresses subsequent testicular maturation; this effect diminishes as androgen is injected on succeeding postnatal days. Testosterone propionate (TP) administered neonatally at dosages up to 3.5 mg appreciably diminished postnatal testicular growth; postpubertal androgen secretion, as assessed by accessory sex organ weights and serum testosterone concentrations and as reflected by a castrationlike developmental pattern of the hepatic enzyme, histidase; spermatogenesis; and fertility. Beyond three mo of age testicular growth rates and androgen secretion--but not fertility--tended to be restored. These effects of neonatal androgen do not require aromatization to estrogen; indeed 5 alpha-dihydrotestosterone elicited more profound testicular suppression than TP, which was sustained until at least 100 days of age. Testes of neonatally androgenized rats were capable of responding to gonadotropins administered at three wk of age with increases in weight and androgen secretion. These findings suggest that a developmental event, suppressible by pharmacologic doses of androgen, occurs at a nontesticular site during the first few post partum days in the male rat; this event programs subsequent testicular maturation.