Reproductive End Research Articles

The Selective Estrogen Receptor Modulator, Raloxifene: An Overview of Nonclinical Pharmacology and Reproductive and Developmental Testing

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. In the ovariectomized (OVX) rat, raloxifene prevents the loss of bone at the distal metaphysis of the femur, proximal tibia, and vertebrae; reduces cancellous bone resorption; and reduces serum cholesterol, but does not cause any significant changes in stromal eosinophilia or uterine epithelium. In estrogen-stimulated OVX rats, raloxifene prevents the morning lowering of serum luteinizing hormone levels, produces a reduction in afternoon serum prolactin levels, antagonizes pituitary weight increase, and antagonizes stimulation of mammary gland development. Raloxifene also has been shown to exhibit antiestrogenic activity in several in vivo and in vitro mammary tumor models. Raloxifene treatment results in regression of endometriosis in both a surgically prepared, rat uterine explant model and in Rhesus macaques diagnosed with spontaneous endometriosis before exposure. Also, uterine leiomyomas in estrogen-stimulated OVX guinea pigs regress after the onset of raloxifene treatment. Raloxifene antagonizes testosterone-induced increases in prostate weight of castrated rats, but does not bind to androgen receptors or affect prostatic 5-α-reductase or testicular steroid 17-α-hydroxylase activity. A series of preclinical toxicology studies was designed to characterize reproductive and developmental outcomes following various schedules of raloxifene treatment in rats or rabbits. Studies of female reproduction and developmental outcome were conducted primarily at pharmacologic doses (0.1, 1, or 10 mg/kg/d); male reproductive studies used higher doses (10, 30, or 100 mg/kg/d). In this series of studies, male reproductive end points were not affected, whereas embryo implantation, fetal rabbit morphology, and several aspects of offspring development were disrupted by the lowest dose of maternal raloxifene treatment, a profile consistent with estrogen antagonist activity.

Human Sexuality in Late Life

Family planning begins at 50 reads the advertisement for a retirement community. Pictured above the caption is an older couple, strolling hand-in-hand on a beach, who have discovered that firn begins after reproduction ends. Aging as a liberator counters the myth that being old means being sick and sexless. However, the idea of sexual activity as lifelong is contrary to the thinking of some older persons, their children, and their physicians. As a result, older adults may be reluctant to admit romantic aspirations; their children may resent a widowed parent's dating; and physicians may not inquire about an elderly patient's sexual history or health for fear of embarrassing the patient. Nonetheless, old age can be looked upon as a period not devoid of sexual pleasures, though myths regarding sex late in life persist [1]. Clinicians who lack an awareness of these myths will find it difficult to treat sexual problems in the elderly.

Prolactin administration to seasonally anestrous mares: reproductive, metabolic, and hair-shedding responses.

Eight pony mares received 4 mg of recombinant porcine prolactin (rpPRL) daily for 45 d beginning on January 15; eight control mares received vehicle. Reproductive end points and various indicators of metabolism, hair shedding, and thyroid activity were monitored. Prolactin concentrations peaked in mares treated with rpPRL at 94 +/- 19 ng/mL 2 h after injection and were 5.1 +/- 1.7 ng/mL 24 h after injection. Treatment with rpPRL increased (P < .01) hair shedding within 14 d, which peaked at 28 d and then dropped precipitously. Binding of 125I-equine prolactin confirmed that antibodies were present in rpPRL-treated mares by 28 d, thus only data up to that time are included herein. The percentage of mares in estrus after 17 d of treatment was greater (P < .05) for mares treated with rpPRL than for controls, although the average day of estrus onset did not differ (P > .1). The date of first ovulation, determined from plasma progesterone concentrations, was hastened (P < .005) in mares treated with rpPRL (February 6 +/- 3 d) relative to control mares (March 14 +/- 6 d). Concentrations of insulin-like growth factor I and nonesterified fatty acids were not affected (P < .05) over time. There were minor differences between groups in thyroid hormone secretion. Various assessments of glucose and insulin indicated no perturbation (P > .1) due to treatment with rpPRL. We conclude that prolactin mediates the onset of vernal hair shedding in mares and is in some way involved with ovulation.

Evolution, mating effort, and crime

AbstructUnlike some psychiatric illnesses, criminal lifestyles are not reproductive dead ends and may represent frequency-dependent adaptations. Sociopaths may gain reproductively from their greater “mating effort” relative to nonsociopaths. This mating-effort construct should be assessed directly in future studies of sociopathy. Collaboration between biologically oriented and environmentally oriented researchers is needed to investigate the biosocial basis of sociopathy.

Contraceptive Policy and Ethics Illustrations from American History

While the technology of long-term contraceptives is relatively new, many of the ethical and policy dilemmas surrounding their use are not. The history of the birth control movement in this country over the past 125 years provides clear examples of the tensions that have always existed between empowering women to control their fertility and promoting limitations on fertility for the disadvantaged. While this is not an exhaustive survey, several important developments in the history of the American birth control movement have been chosen to illustrate these tensions. In the late nineteenth century, Victorian opinion tolerated promiscuity among men and promoted sexual self-control among women. Prostitutes were a common and accepted solution to this dichotomy. Despite the view that female sexuality was to serve the end of reproduction rather than the woman's pleasure, contraception was widely practiced among all social classes. The methods employed varied by class, however, due to cost and availability. The upper classes were more likely to use relatively expensive methods of contraception such as condoms, spermicides, and douches. They might also have had access to diaphragms and cervical caps, which were smuggled in from Europe at a high cost. Withdrawal and rhythm were often the only methods available to the poor. In an era when menstrual cycles were poorly understood, pregnancies often resulted. Abortion, often self-induced and always dangerous, was resorted to frequently. It is estimated that by the 1850s one out of every five to six pregnancies in America ended with an abortion.[1] Mortality from septic abortions was extremely high. In 1888, death from abortion was estimated to be fifteen times greater than maternal mortality.[2] During this era, American feminists supported the concept of motherhood.[3] Far from empowering women and providing them with sexual freedom, however, voluntary motherhood sustained traditional family roles for women. According to this concept, limiting family size enhanced women's ability to fulfill their societal roles as wives and mothers. Feminists were joined by moral reformers, who were concerned about excessive breeding among the lower classes, particularly immigrants. Targeting the lower class and members of minority groups in the effort to reduce fertility has strong historical roots in the late nineteenth century. Although contraception was widely practiced in private, many were not willing to risk public expressions of support for it or admit to its use. This reluctance influenced public policy. Abortion was declared illegal for the first time in the United States in 1830. A majority of states had declared it so by 1970.[4] A great legal blow was dealt to contraception in 1873 with the passage of what came to be known as the Comstock laws - a federal statute that made it illegal to transport obscene materials through the mail. Contraceptive devices such as condoms and diaphragms, as well as sexually explicit literature, were confiscated under this law. It took the work of one of birth control's leading proponents, Margaret Sanger, to weaken its effects. Margaret Sanger and the Movement for Planned Parenthood Perhaps no name is more closely associated with birth control, family planning, and reproductive freedom for women than Margaret Sanger. The daughter of Irish immigrants, Sanger was born in 1879 and played a strong role in the birth control movement in the United States and abroad until her death in 1966. While she promoted access to birth control for all women, she focused particularly on the poor, as upper-class women had some access to contraception from their private physicians. Poor women did not. Sanger believed that uncontrolled fertility and large families were inextricably linked to poverty. Her efforts to empower poor women, however, had affinities with the eugenics movement. Many eugenicists supported the idea of limiting population growth, particularly among those they viewed as undesirable. …

Reproductive Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Male Rats: Different Effects of in Utero Versus Lactational Exposure

The male rat reproductive system is highly sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) when exposure occurs during fetal and neonatal development. Our objective was to determine the relative contributions of in utero versus lactational TCDD exposure to effects on male reproductive function. Pregnant Holtzman rats were treated on Day 15 of gestation with TCDD (1.0 μg/kg) or vehicle (control). At birth litters were standardized to five males and five females and fostered to dams of the same treatment or cross-fostered to darns of the opposite treatment. Four treatment groups were assessed: male offspring not exposed to TCDD by either route (control) and male offspring exposed to TCDD in utero (IU), via lactation (L), or in utero and via lactation (IUL). During early postnatal development, two androgen sensitive end points, relative anogenital distance and time to testis descent, were not affected by TCDD. However, end points evaluated later during development were altered. Time to separation of the prepuce from the glans penis (an index of pubertal development) was delayed, plasma testosterone concentrations and accessory sex organ weights were reduced, daily sperm production and epididymal sperm reserves were decreased, and sexual behavior was feminized. Certain responses were only produced by IU exposure whereas other responses only occurred following L exposure. Only IU TCDD exposure delayed pubertal development and decreased daily sperm production, while only L TCDD exposure feminized the sexual behavior of male offspring. For most male reproductive end points both IU and L TCDD exposure produced the same responses. Decreases in plasma testosterone concentrations, reductions in weights, protein, and DNA contents of ventral prostate and seminal vesicles, and decreases in epididymal sperm reserves were caused in young adult rats by either IU or L exposure to TCDD. We conclude that the route and timing of TCDD exposure during fetal and neonatal development of the rat determine the profile of male reproductive effects observed and that all effects in the present study, with the notable exception of feminized sexual behavior, can be caused by low level exposure to TCDD via the IU route alone.

Effect of toxins 544 and 514 from Karwinskia humboldtiana (buckthorn) plant upon fetal development of the mouse

R. Valadez-Alvizo, A. Rodríguez-Alvarado, L. Martínez de Villarreal, R. González-Alanís and A. Piñeyro-López. Effect of toxins 544 and 514 from Karwinskia humboldtiana (buckthorn) plant upon fetal development of the mouse. Toxicon 31, 1329–1332, 1993.—The teratogenic effect of toxins 544 and 514 from K. humboldtiana upon the mouse embryo was evaluated. One half of the ld 50 dose for the mouse was administered at day 8 of gestation. At the end of pregnancy, reproduction and fetal data were recorded. Dams treated with toxin 544, but not with toxin 514, showed a higher incidence of reabsorptions, malformations, as well as lower fetal length compared to the control group.

Rotifers in aging research: use of rotifers to test various theories of aging

Four theories of aging are discussed to examine how effectively they might explain the aging process in rotifers. One of the early theories, the rate of living theory of aging can perhaps be discounted. Although the theory predicts that increased biological energy expenditure, in the form of increased activity or reproduction, would lead to a shorter lifespan, these predictions are not born out by experimental evidence. At the whole animal level, a case can be made for a theory of programmed aging, where the end of reproduction signals the end of the lifespan. Support for this view comes from the observation that lifespan is positively correlated with reproductive parameters, that treatments that extend lifespan usually act to extend the reproductive period, and that the end of reproduction is associated with high mortality and senescent biochemical changes. Two molecular theories of aging are also discussed; the free radical theory of aging and the calcium theory of aging. These theories point to the fact that molecular damage accumulates and that calcium influx increases in the course of aging. When free radical buildup or calcium homeostasis is reduced, lifespan is extended. A molecular explanation of aging does not necessarily exclude the idea of programmed aging. It is probable that an eventual understanding of the aging process will rest on both a physiological and molecular basis.

Assessing sublethal levels of sediment contamination using the estuarine amphipod Leptocheirus plumulosus

AbstractRecent emphasis on the incorporation of sublethal end points into sediment toxicity test methods follows the realization that acute lethality tests may not provide sufficient sensitivity for predicting subtle ecological effects of sediment contamination. To this end, a partial life‐cycle test with the amphipod Leptocheirus plumulosus Shoemaker was evaluated for solid‐phase testing of contaminated estuarine sediments. Initially, juvenile and adultLeptocheirus plumulosus and the amphipod Hyalella azteca were exposed to gradients of chemical contamination prepared by diluting field‐collected contaminated sediment with texturally similar reference sediment. Ten‐day exposure results indicate juvenile Leptocheirus plumulosus is more sensitive than adult Leptocheirus plumulosus and Hyalella azteca, with significant mortality of juvenile Leptocheirus plumulosus occurring in sediment diluted to 12.5% of the adult lowest‐observed‐effect concentration (LOEC). Long‐term exposure (30 d) of juveniles to dilutions of the acute juvenile LOEC shows significant effects on growth in sediment concentrations below the lethal threshold. Effects on reproductive end points (proportion of gravid females, number of young) parallel growth effects. Evaluation of nontoxicant experimental variables indicates significant effects of temperature and feeding regime on sensitivity of juvenile Leptocheirus plumulosus to contaminated sediment.

Prostaglandin E2 and reproduction in the male crested newt, Triturus carnifex (Laur.)

AbstractPlasma prostaglandin E2 (PGE2) and sex hormones (progesterone, androgens, and 17β‐estradiol) were determined in the male crested newt, Triturus carnifex, during the annual sexual cycle. In vivo experiments were carried out to study the effects of PGE2 on plasma sex hormones during prereproduction, reproduction, and postreproduction; contemporaneously, in vitro experiments were performed to study the effects of PGE2 on the testicular release of sex hormones. The effects of one week's captivity on PGE2 and sex hormones was also evaluated. Plasma PGE2 increases in autumn, during the recovery of gonad and secondary sexual characteristics; it peaks in January, at the start of reproduction, and decreases during reproduction to peak again in April, at the end of reproduction. Plasma sex hormones show trends similar to those found in previous studies. In autumn, PGE2 and androgen patterns are positively correlated, whereas the April PGE2 peak coincides with a drop in plasma androgens. In vivo and in vitro experiments suggest the causal relation between PGE2 and androgens. When injected in prereproductive newts or added to cultured testis in this period, PGE2 increases androgen production. An opposite in vivo and in vitro effect is obtained during reproduction. These findings suggest that PGE2 is involved in inducing the autumnal recovery of gonad and secondary sexual characters (through the stimulation of androgen production), and in terminating the breeding processes (through the inhibition of androgen production and/or clearance). Finally, captivity causes a decrease of plasma PGE2, androgens, and estradiol, a phenomenon quite common in captive vertebrates. © 1992 Wiley‐Liss, Inc.

Adverse pregnancy outcome and childhood malignancy with reference to paternal welding exposure.

Welding may deteriorate spermatogenesis and increase reproductive failures. This study examines reproductive end points in a Danish cohort of 10,059 metalworkers who fathered 3,569 children in 1973 through 1986. Occupational histories were gathered by postal questionnaires. Information on pregnancy outcomes and offspring was obtained by record linkage to medical registers. The occurrence of reduced birthweight, preterm delivery, infant mortality, and congenital malformation was not increased among children at risk from paternal welding exposure in comparison with children not at risk. The overall incidence of childhood malignancies among 23,264 children born in 1968 through 1986 with a total of 259,113 person-years of follow-up was equal to national rates (relative risk 0.97, 95% confidence interval 0.63-1.42). However, pregnancies preceding a birth at risk from paternal exposure to stainless steel welding were more often terminated by spontaneous abortion (odds ratio 1.9, 95% confidence interval 1.1-3.2). This finding needs cautious interpretation and should be further investigated in future studies.

PGF2 α, PGE 2, and sex steroids from the abdominal gland of the male crested newt Triturus carnifex (Laur.)

Prostaglandin F 2 α ( PGF 2 α ), prostaglandin E 2 (PGE 2), progesterone, androgens, and 17 β-estradiol in vitro release by the abdominal gland of the crested newt, Triturus carnifex (Laur.), was studied during the prereproductive, reproductive and postreproductive periods. In addition, the in vitro effects of the PGF 2 α and/or PGE 2 on progesterone, androgens and estradiol release by the abdominal gland were evaluated. PGF 2 α , PGE 2 and progesterone release was higher during the reproductive period, and in the same period, PGE 2 treatment induced a progesterone increase. PGF 2 α induced an increase of abdominal gland estradiol release at the end of the reproductive period. These results seemed to confirm the pheromonal role assigned to progesterone, and suggested a PGE 2 stimulatory role in inducing progesterone release, even if pheromonal activity of PGF 2 α and PGE 2 cannot be excluded. In addition, PGF 2 α -dependent estradiol increase at the end of reproduction could be interpreted as a mechanism for interruption of the abdominal gland activity.

Testing sediment toxicity in chesapeake bay with the amphipod Leptocheirus plumulosus: An evaluation

AbstractOrganisms selected for testing the toxicity of estuarine sediments must exhibit sensitivity to toxicants while remaining tolerant of wide ranges of salinities and sediment characteristics. The amphipod Leptocheirus plumulosus Shoemaker is an ecologically important infaunal inhabitant of Chesapeake Bay sediments. Leptocheirus plumulosus was exposed to a range of salinities and sediments varying in physical composition for up to 28 d in separate experiments to determine effects of natural environmental variables on amphipod survival and reproduction. No significant differences in adult survival were observed among salinity treatments ranging from 1.5 to 32 ppt or among sediment treatments varying in particle size and organic content. Significant effects on reproductive end points were detected, indicating the potential for incorporating sublethal end points into the bioassay. Acute 96‐h LC50 values for aqueous cadmium at a salinity of 6 ppt were determined for Leptocheirus plumulosus and the amphipod Hyalella azteca Saussure, an organism commonly used in freshwater sediment toxicity tests. The LC50 values were 0.30 mg Cd per liter and 0.19 mg Cd per liter for Leptocheirus plumulosus and Hyalella azteca, respectively.

The reproductive lifespan of Onchocerca volvulus in West African savanna

The epidemiological model ONCHOSIM — a model and computer simulation program for the transmission and control of onchocerciasis — has been used to determine the range of plausible values for the reproductive lifespan of Onchocerca volvulus. Model predictions based on different lifespan quantifications were compared with the results of longitudinal skin-snip surveys undertaken in 4 reference villages during 13 to 14 years of successful vector control in the Onchocerciasis Control Programme in West Africa. Good fits between predicted and observed trends in skin microfilarial loads could be obtained for all villages. It is concluded that the reproductive lifespan of the savanna strain of O. volvulus lies between 9 and 11 years, and that 95% of the parasites reach the end of reproduction before the age of 13 to 14 years.

Comparative morphology of acrogenous branch systems and phylogenetic considerations. II. Angiosperms

A concept for a primitive angiospermous branch system is given in order to have a starting point for the derivation of the diverse and highly differentiated branch systems observed in contemporary angiosperms. Hitherto Troll's (1964, 1969) comparative study of the synflorescences in this plant group — developed out predominantly on herbaceous plants — was the most comprehensive and sophisticated treatment dealing with branch systems. Unfortunately, the work on tropical tree architecture by Halle et al. (1978) has no reference to the classical studies of Troll and his pupils. Thus Muller-Doblies and Weberling (1984) emphasized the high degree of terminological incompatibility between the two works. Angiosperms are seen as a monophyletic plant division. Consequently, the branch system of the first primitive angiosperms must be the starting point in the evolution of the abundant diversity of branch systems and growth forms of modern angiosperms. If it is accepted that primitive angiospermous shoots were terminated by a large flower, one may assume, that the reproductive end of the shoot was enriched by paracladia early in evolution, thereby developing a terminal inflorescence instead of a single flower. Thus the primitive shoot unit was divided into a basal vegetative region — the trophotagma, branching retardively — and the reproductive terminal region, the anthotagma, branching simultaneously. It is demonstrated through a selection of different examples, that the construction of such a system possesses the options for several modifications, enabling the evolution of the abundant diversity of branch systems which characterizes contemporary angiosperms.

Overview of reproductive and developmental toxicity studies of 1,3-butadiene in rodents.

A series of studies to further evaluate the developmental and reproductive toxicity of inhaled 1,3-butadiene was sponsored by the National Toxicology Program. Pregnant Sprague-Dawley rats (24-28/group) and Swiss (CD-1) mice (18-22/group) were exposed to atmospheric concentrations of 0, 40, 200, or 1000 ppm 1,3-butadiene for 6 hr/day on days 6 through 15 of gestation (dg) and killed on dg 18 (mice) or dg 20 (rats). Subsequently, the uterine contents were evaluated; individual fetal body weights were recorded; and external, visceral, and skeletal examinations were performed. In rats, maternal toxicity was observed in the 1000-ppm group in the form of reduced extragestational weight gain and, during the first week of treatment, decreased body weight gain. Under these conditions, there was no evidence of developmental toxicity in rats. In contrast, results of the mouse developmental toxicity study indicated that the fetus may be more susceptible than the dam to inhaled 1,3-butadiene. Maternal toxicity was observed in mice at the 200- and 1000-ppm 1,3-butadiene exposure levels, whereas 40 ppm and higher concentrations of 1,3-butadiene caused significant exposure-related reductions in the mean body weights of male fetuses. Mean body weights of female fetuses were also reduced at the 200- and 1000-ppm exposure levels. No increased incidence of malformations was observed in either study. Other studies addressing male reproductive and mutagenesis end points were performed with B6C3F1 mice (sperm-head morphology) and Swiss (CD-1) mice (dominant lethal study).(ABSTRACT TRUNCATED AT 250 WORDS)

Statistical Analyses of Reproductive and Developmental Toxicology Studies

Regulatory requirements for the development of commercial products include assess­ ments of potential effects on reproductive function and development of the conceptus. The experimental tests employed in these assessments are complex in design and have numerous experimental end points that require sophisticated methods for their statistical analysis. This manuscript discusses biological and statistical aspects of these data and presents a compilation of methods for their statistical analyses. The discussion includes analyses of maternal toxicity data, estrous cycle data, novel reproductive toxicity end points (germ cell evaluations, hormone levels), and devel­ opmental toxicity (teratology) data (fetal malformations or lethality, fetal weight, postnatal evaluations). The suggested methods are offered as tools for assisting scientists in the interpretation of experimental results.

Exochomus troberti Mulsant (Coleoptera: Coccinellidae): A predator of cassava mealybug, Phenacoccus manihoti Mat-Ferr (Homoptera:Pseudococcidae) in southeastern Nigeria

The developmental periods of the immature stages of Exochomus troberti Mulsant were studied in the laboratory at the prevailing temperature range of 26–30°C. That of the second instar larva was the shortest (2.1 days) followed by the third instar larva (3.1 days). The longest developmental period (approximately 5 days) was recorded for the egg, first- and fourth-instar larvae and pupa. Oviposition commenced after 1 week of adult life and peaked in the 5th week with 37.2 female eggs/female. All ovipositing females survived the first 9 weeks of adult life when 82% of the total eggs were laid. By the 13th week, which was the effective end of reproduction (98 % fecundity) only 40% of the females had died. Both capacity for increase (rc) and intrinsic rate of increase (rm) were calculated for E. troberti and found to be 0.092/day and 0.105/day, respectively. Mean daily predation rates in non-choice experiments on the second instar nymphs of P. manihoti by the fourth, third and second instar larvae of E. troberti were 28.3, 15.6 and 8.0, respectively. On the third instar nymphs and fourth instar young adults of P. manihoti the mean daily predation rates by the fourth, third and second instar larvae of E. troberti Were 17.6, 8.3 and 4.5; and 4.0, 3.0 and 1.0, respectively. The populations of E. troberti, other coccinellid predators and P. manihoti were monitored in two small local farms for three seasons. E. troberti was found to be the dominant coccinella predator in terms of numbers of individuals found in the field during the years of this experiment. The cyclical population oscillations of P. manihoti were similar in all the experimental years but differed only in the amplitude of oscillations. Those of E. troberti and the other coccinellid predators were lower than those of P. manihoti.

Like father, like son: Parental models and influences in the making of masculinity at an english public school, 1929–1950

This paper is about the way a small group of parents brought up their sons, as revealed in their letters to the headmaster of a public school between 1929 and 1950. For them masculinity was about enabling their sons to enter a suitable occupation, preferably the professions, and schooling was a pragmatic means to the end of social reproduction and mobility. They employed diverse and often ingenious strategies in which the whole family was involved. Contemporary theories of child rearing were based on Freudian psychology. They emphasised the need for constant maternal attention in emotional development and regarded fathering as marginal to adequate parenting. The empirical evidence presented suggests that for those adolescent boys their fathers' influence was all-important and that of their mothers marginal.

Evaluation of reproductive parameters in adult male Wistar rats after subchronic exposure (gavage) to benomyl.

Proven-breeder 102-d-old male Wistar rats were gavaged daily with 0, 1, 5, 15, or 45 mg/kg.d benomyl. The animals were bred to untreated females after 62 d and killed after 76-79 d for evaluation of selected male reproductive end points. Minimal to moderate changes were observed in rats dosed with 45 mg/kg.d; these included decreased testis and epididymis weight, reduced cauda sperm reserves, decreased sperm production, increased numbers of decapitated spermatozoa, and increased numbers of seminiferous tubules containing multinucleated giant cells. Reproductive performance, seminal vesicle and prostate weight, sperm motility, serum luteinizing hormone, follicle-stimulating hormone, prolactin, and androgen binding protein were not affected by any of the dosages tested. Based on these end points, the no-effect level was 15 mg/kg.d.