Period of maximal susceptibility to behavioral modification by testosterone in the golden hamster

Male hamsters castrated on the day of birth (Day 1) and female hamsters were treated with the free form of testosterone (100 μg/day) on Days 1 and 2, 3 and 4, 5 and 6, 7 and 8, or 9 and 10 postnatally. Following androgen treatment in adulthood, animals treated on Days 1 and 2 or 3 and 4 showed significantly higher mounting and intromission frequencies than animals treated later in life. Sexual receptivity measures following ovarian hormone treatment showed no differences among the male groups, whereas females treated on Days 1 and 2 or 3 and 4 were significantly lower in sexual receptivity measures than females in other treatment groups. Histology of the adult ovaries indicated no modification of normal function in any treatment group. In a subsequent experiment, Day 1 castrated male and intact female hamsters were treated with the free form of testosterone on Days 1–5 (40 or 100 μg/day), 6–10 (40 or 100 μg/day), or Days 1–10 (50 μg/day). Masculine behavior measures were significantly higher in males treated Days 1–10 than in other groups. Among the females, masculine behavior was highest in those treated Days 1–5 postnatally. Sexual receptivity in both males and females was significantly depressed by testosterone treatment Days 1–10 postnatally. Ovarian histology also revealed alterations in gonadal function in females treated Days 1–5 and 1–10 postnatally. Compared with previously published findings, these data suggest that testosterone can be as effective in inducing behavioral masculinization and defeminization as testosterone propionate, provided that treatment extends over a prolonged period during early postnatal development.     

A decrease in thymus-mediated immune responses as a result of treatment of neonatal rats with glutamate

We investigated whether administration of monosodium l-glutamate (MSG) to neonatal rats would disrupt immune responses in intact and orchidectomized adult male rats. Neonatal male rats were treated with saline or MSG which causes severe endocrine abnormalities. Half of each group of animals were orchidectomized as adults and killed one week later along with intact rats. MSG treatment resulted in suppressed serum LH levels in intact rats. Thymus weight and spleen cellularity in intact animals were not affected by MSG treatment, but thymus weight increased within one week after orchidectomy in both saline- and MSG-treated groups. In intact rats, lymphocyte stimulation by the T cell specific mitogens (concanavalin A or phytohemagglutinin) or the B cell specific mitogen (lipopolysaccharide) was unaffected by prior treatment with MSG. However, MSG treatment blocked the decrease attributable to orchidectomy in concanavalin A and phytohemagglutinin stimulation of lymphocyte blastogenesis. The results suggest that administration of MSG to neonatal male rats can alter some immune responses in the adult animal.     

谷氨酸单钠透过胎盘屏障对仔鼠特定脑区的结构和功能的影响

３－Ｇｌｕ示踪实验表明,谷氨酸可以透过胎盘屏障进入胎鼠体内,较均一地分布于中枢神经系统及内脏各器官。给母鼠隔日注射高、低剂量的谷氨酸单钠（ＭＳＧ,２．５ｍｓ／ｇ,１．０ｍｇ／ｇ）至分娩,对成年后的仔鼠进行检测发现,高剂量组仔鼠记忆能力及Ｙ－迷宫空间分辨学习能力均严重受损,下丘脑弓状核及腹内侧核神经元被明显破坏,出现胞质肿胀、核固缩、神经元数目减少。孕期ＭＳＧ处理还可以使仔鼠下丘脑和海马３Ｈ－Ｇｌｕ受体－配体结合量显著变化。采用ＡＲ－ＣＭ－ＭＩＣ阳离子检测系统观察单个神经元内游离Ｃａ２＋浓度（［Ｃａ２＋］ｉ）的变化时还发现,ＭＳＧ可以通过诱发胞外Ｃａ２＋内流及胞内钙库释放Ｃａ２＋来增高［Ｃａ２＋］ｉ。以上结果提示：ＭＳＧ对仔鼠的剂量依赖性神经毒性作用可能与其过度激活膜谷氨酸受体,引起细胞内Ｃａ２＋超载,最终导致特定脑区的神经元发生溃变甚至死亡有关,而这些变化可能正是仔鼠成年后学习记忆受损的原因。     

Effect of diphenylhydantoin administered during gestation and lactation on the motor development and cerebellar histology of the young rat]

Rattus norvegicus females were treated by diphenylhydantoin (D.P.H.), all along pregnancy and lactation. 4 groups were constituted: a 100 mg DPH/kg/day group, a 50 mg DPH/kg/day group; a placebo group (treated with pure water), and control group. D.P.H. was given twice a day by a gastric tube. The cerebellar Purkinje cells studied through light microscopy and transmission electron microscopy in young rats (25 days old) showed no visible alteration. 2 motorcoordination tests were applied to the young rats, during their 2nd and 3rd weeks of post-natal life. Young rats of DPH 100, DPH 50 and placebo groups showed a backwardness relatively to control. This backwardness may be attributed to the maternal forced feeding stress, but not to a specific action of the DPH.     

The effect of neonatal administration of monosodium glutamate on behavior and blood corticosterone level

DBA/2 male mice were treated with monosodium glutamate (MSG) in a dose of 4 mg/g on 1, 3, 5, 7, 9 days after birth. Saline treated and intact males were used as control groups. MSG treated males displayed decreased number of crossed squares, rearings, entries in the centre and time in the centre of open field in comparison with saline-treated but not intact animals. Time in the light compartment of the light-dark box was increased in MSG-treated mice versus both saline treated and intact animals. MSG administration reduced acoustic startle response but did not affect the magnitude of prepulse inhibition of the startle reflex. Sexual motivation in male mice was reduced by MSG, the same trend was observed after saline treatment. MSG administration increased corticosterone basal level 4-fold while saline treatment did not affect it. These data suggest that neonatal administration of MSG decreases locomotion, exploratory activity, anxiety in male mice, while corticosterone level is increased. Saline treatment increases these parameters (except sexual motivation), and this augmentation is not connected to changes in corticosterone basal level.     

Effects of neonatal septal lesions on reproductive behavior of male and female rats

The purpose of this study was to examine the effects of neonatally placed septal lesions (SL) in male, female, and androgenized female rats on reproductive behavior. Animals were castrated as adults and tested for both feminine and masculine sexual behavior. After treatment with estradiol benzoate (EB) alone (2 μg daily for 3 days), only the females with SL which had not been given testosterone propionate (TP) neonatally showed a facilitation of lordosis behavior. Following EB (2 μg for 3 days) plus 0.5 mg progesterone (P), both the lesioned and the sham-operated female groups showed an increase in the display of lordosis in either hormonal condition. All animals were given a pretest for masculine sexual behavior and tested on Days 4, 7, 11, and 15 of daily TP treatment (150 μg/day). There was no effect of the neonatally placed SL on masculine sexual behavior in female rats or in female rats androgenized with 30 μg TP. However, lesioned females treated neonatally with 1 mg TP showed a marginal enhancement of masculine sexual behavior. Male rats given SL neonatally showed a marked enhancement of masculine sexual behavior compared to that of controls. These results suggest that, depending on the neonatal hormone environment, SL selectively increase behavioral sensitivity to hormones. Although neonatally lesioned females show behavioral responses similar to females given SL as adults, male rats given SL neonatally are unique in that they show enhanced masculine sexual behavior whereas males lesioned as adults do not.     

Lack of effect of vaginal lavages and aliphatic acids on ejaculatory responses in rhesus monkeys: Behavioral and chemical analyses

Four behavioral experiments involving a total of 19 adult male and 27 adult spayed female rhesus monkeys failed to reveal significant sexual stimulatory properties of vaginal lavages obtained from estrogen-treated donor females when the material was applied to spayed nonestrogenized recipient females. However, all but one of the males copulated to ejaculation when paired with estrogenized females. Two of three males showed moderate increases in sexual behavior with recipients when the vaginal lavage tested was contaminated with 24-hr-old ejaculate. When purified aliphatic acids were applied to spayed nonestrogenized recepients, one of two males showed increased frequencies of mounting behavior, but intromissions and ejaculations were not displayed.Quantitative analyses of short chain aliphatic acids in vaginal lavages, the hypothesized active component, revealed that (a) spayed females had nondetectable levels of aliphatic acids; (b) daily estradiol benzoate treatment for 6–10 days (25 μg/day i.m.) induced detectable levels of acetic, propionic, and butyric acids; (c) exposure to estradiol for six months resulted in a fairly constant plateau of aliphatic acid concentrations; and (d) ejaculate from the male caused up to fivefold elevations in the aliphatic acid concentrations.Three intact females were studied throughout a menstrual cycle, and the peak values of aliphatic acids occurred in the luteal phase, several days after presumed ovulation. Three spayed females treated chronically with estradiol were given four daily injections of 5 mg progesterone, and the mean concentrations of aliphatic acids increased from 199.7 to 801.0 μg/ml. However, the endocrine conditions associated with maximum concentrations of aliphatic acids in either intact or spayed females are known from other studies to be associated with decreased likelihood of copulation.We conclude that for the majority of males studied, the application of vaginal lavages obtained from estrogenized donors did not significantly increase copulatory behavior with spayed, nonestrogenized recipient females. Moreover, the data from aliphatic acid determinations suggest that increases in concentrations of these substances are not always associated with facilitation of copulation, since the largest increases were found either (1) following copulation to ejaculation, (2) during the luteal phase in cycles free of copulation, or (3) following progesterone treatment of spayed, estrogenized females. Finally, comparison of our results with those from other laboratories suggests that the mechanism involved in positive effects may depend upon associative learning or upon extinction and disinhibition of sexual interest.     

Resistance training restores metabolic alterations induced by monosodium glutamate in a sex-dependent manner in male and female rats

Despite resistance exercises being associated with health outcomes, numerous issues are still unresolved and further research is required before the exercise can faithfully be prescribed as medicine. The goal of this study was to investigate whether there are sex differences in resistance training effects on metabolic alterations induced by monosodium glutamate (MSG), a model of obesity, in male and female rats. Male and female Wistar rats received MSG (4 g/kg body weight/day, s.c.) from postnatal day 1 to 10. After 10 days from MSG administration, the rats were separated into two groups: MSG-sedentary and MSG-exercised. At postnatal day 60, the animals started a resistance training protocol in an 80 degrees inclined vertical ladder apparatus and performed it for 7 weeks. Control rats received saline solution and were divided in saline-sedentary and saline-exercised. Resistance training restored all plasma biochemical parameters (glucose, cholesterol, triglycerides, aspartate aminotransferase, and alanine aminotransferase) increased in male and female rats treated with MSG. The MSG administration induced hyperglycemia associated with a decrease in the skeletal muscle glucose transporter 4 (GLUT4) levels and accompanied by deregulation in proteins, G-6Pase, and tyrosine aminotransferase, involved in hepatic glucose metabolism of male and female rats. MSG induced dyslipidemia and lipotoxicity in the liver and skeletal muscle of male rats. Regarding female rats, lipotoxicity was found only in the skeletal muscle. The resistance training had beneficial effects against metabolic alterations induced by MSG in male and female rats, through regulation of proteins (GLUT2, protein kinase B, and GLUT4) involved in glucose and lipid pathways in the liver and skeletal muscle.     

Immunoreactive 7B2 concentrations in rats with various endocrine conditions

Changes in 7B2 immunoreactivity in the pituitary as well as in the other brain regions and gut after various endocrine situations were investigated. Gonadectomy and neonatal monosodium glutamate (MSG) treatment resulted in an appreciable increase in the pituitary 7B2 concentration, though 7B2 content in the MSG treated pituitary was not significantly different when calculation was performed on a per pituitary gland basis. The 7B2 concentration in the cerebellum, midbrain and cortex in thyroxine treated rats showed a significant increase, which might indicate possible thyroid hormone involvement in 7B2 metabolism in the brain. The pituitary 7B2 concentration during the estrous cycle did not change significantly. These results suggest that pituitary 7B2 may correlate to the pituitary gonadotropins and that brain 7B2 content may be modulated by thyroid hormones.     

Estrogen plus androgen induced mounting in adult female hamsters

This study demonstrated that the combined administration of estrogens and androgens activates the display of mounting by female hamsters. Forty-nine ovariectomized hamsters were injected daily with either estradiol benzoate (EB, N = 8); dihydrotestosterone propionate (DHTP, N = 7); testosterone propionate (TP, N = 6); androstenedione (AD, N = 9); EB plus DHTP (N = 10); or estrone plus DHTP (E₁ + DHTP, N = 9). All androgens were administered at a dose of 1 mg per day for the first 24 days and at a dose of 2 mg per day for the last 14 days. The EB dose was 6 μg per day and the E₁ dose was 100 μg per day. Females were tested for male behavior once a week starting on Day 10 of injections and for female behavior on Day 39.One hundred percent of EB + DHTP treated females; 67% of the E₁ + DHTP treated females; 55% of the AD treated females; 33% of the TP treated females; 29% of the DHTP treated females; and none of the EB treated females mounted during at least one test. Only one of the E₁ + DHTP treated females showed the intromission pattern; otherwise most females which mounted displayed the intromission pattern. The median number of days preceding the onset of mounting ranged from 21 to 31 days and did not differ among treatment groups.     

Effects of acute X-irradiation on pre-implantation embryos and on the implantation reaction in the mouse

Summary Pregnant mice were treated on the 1st, 2nd, and 3rd day of pregnancy by a single dose of 300 R X-rays. Uterine dissections at day 6 p.c. topographically revealed decrease of the implantation sites from 9.67 per female in the controls to 8.00 in females irradiated on day 1, to 6.63 in females irradiated on day 2, and to 7.00 in females irradiated on day 3 p.c. Among a number of 22 implantations after irradiation on day 1, 19 after irradiation on day 2 and 11 after irradiation on day 3, however no living embryo could be detected on histological examination. The degree of damage as indicated by the total resorptions was highest (94,7%) after irradiation on day 2 p.c., and lowest (31,8%) after irradiation on day 1 p.c. Since the decidual cell reaction was either unaffected or only slightly reduced after irradiation on day 2 p.c. as indicated by cytomorphological criteria and the alkaline phosphatase reaction, not maternal effects but direct effects only of the irradiation on the embryo must account for embryonic deaths.     

Obesity and changes of alkaline phosphatase activity in the small intestine of 40- and 80-day-old rats subjected to early postnatal overfeeding or monosodium glutamate

To investigate the relationship between development of obesity and the small intestinal functions two experimental models of male Wistar rats were used in the present work: 1) early postnatally overfed rats, nursed from birth to weaning in small litters (SL, 4 pups/nest), and 2) neonatally monosodium glutamate treated rats (MSG 2 mg/g b.w. administered s.c. for 4 days after birth) submitted to the same early nutritional manipulation. After weaning, all animals had free access to a standard pellet diet and at 40 and 80 days of age their body weight, body fat content and food consumption as well as changes of the brush-border-bound duodenal and jejunal alkaline phosphatase (AP) activity were compared with parameters of the offsprings raised under normal feeding conditions (NL, 8 pups/nest). At 40 and 80 days of age the postnatally overfed pups from SL nests became heavier, displayed a significantly increased epididymal plus retroperitoneal fat pad weight (P<0.01) and significantly higher AP activity in both segments of the small intestine (P<0.01) in comparison with rats nursed in NL nests, although their mean daily food intake did not differ from that of non-obese rats during the postweaning periods examined. In contrast, the same treatment of MSG rats had only a small effect on late appearance of obesity, i.e. in early postnatally overfed and normally fed MSG rats a similar pattern of body weight, food intake, adiposity and AP activity was found after weaning. The effect of MSG-treatment was also accompanied by the appearance of normophagia, hypophagia and stunted growth on day 40 and day 80, respectively. Moreover, the size of fat depots and the increase of brush-border-bound AP activity in MSG rats belonging to the SL and NL groups was quantitatively similar to the values size of these parameters observed in SL obese rats subjected to early postnatal overnutrition. These results indicate that postnatal nutritional experience (overnutrition) may represent a predisposing factor in control rats from small litters for the development of obesity in later life. Permanently increased small intestinal AP activity observed after weaning in both models of obesity when hyperphagia is not present suggest that these functional changes and associated alterations in food digestion could be a component of regulatory mechanisms contributing to the maintenance of their elevated body fat weight.     

Differential sensitivity of mounting and lordosis control systems to early androgen treatment in male and female hamsters.

The effects of early testosterone propionate (TP) treatment on the adult sexual behavior of hamsters were investigated in two experiments. In Expt. I, male and female pups were injected with oil vehicle or 1, 5, 10, 50, 100, or 250 μg of TP 24 hr after birth. In Expt. II, males and females received either oil or 10 μg of TP on the day of birth (Day 1), Day 3, Day 5, Day 7, or Day 9. At 70 days of age all animals were gonadectomized and 10 days later tested for lordosis behavior after estrogen and progesterone priming. One week after the test for female behavior all females began receiving 500 μg of TP each day and were tested for mounting and intromission behavior three times at 10 day intervals. Lordosis behavior was inhibited by as little as 5 μg of TP given 24 hr after birth. In males this dose produced the maximal effect, but in females increasing dosages resulted in a proportional decrease in lordosis duration. One μg of TP neonatally facilitated later mounting and intromission behavior in females and 250 μg of TP was no more effective than 1 μg. Lordosis duration was inhibited in females by 10 μg of TP on either Day 1 or 3, however, mounts and intromissions were facilitated by TP treatment on Day 1, 3, 5 or 7. These experiments demonstrate that the mechanisms mediating masculine behavior are more sensitive to neonatal TP treatment than are the mechanisms mediating lordosis behavior.     

Oral administration of MSG increases expression of glutamate receptors and transporters in the gastrointestinal tract of young piglets

Glutamate receptors and transporters, including T1R1 and T1R3 (taste receptor 1, subtypes 1 and 3), mGluRs (metabotropic glutamate receptors), EAAC-1 (excitatory amino acid carrier-1), GLAST-1 (glutamate-aspartate transporter-1), and GLT-1 (glutamate transporter-1), are expressed in the gastrointestinal tract. This study determined effects of oral administration of monosodium glutamate [MSG; 0, 0.06, 0.5, or 1 g/kg body weight (BW)/day] for 21 days on expression of glutamate receptors and transporters in the stomach and jejunum of sow-reared piglets. Both mRNA and protein levels for gastric T1R1, T1R3, mGluR1, mGluR4, EAAT1, EAAT2, EAAT3, and EAAT4 and mRNA levels for jejunal T1R1, T1R3, EAAT1, EAAT2, EAAT3 and EAAT4 were increased (P < 0.05) by MSG supplementation. Among all groups, mRNA levels for gastric EAAT1, EAAT2, EAAT3, and EAAT4 were highest (P < 0.05) in piglets receiving 1 g MSG/kg BW/day. EAAT1 and EAAT2 mRNA levels in the stomach and jejunum of piglets receiving 0.5 g MSG/kg BW/day, as well as jejunal EAAT3 and EAAT4 mRNA levels in piglets receiving 1 g MSG/kg BW/day, were higher (P < 0.05) than those in the control and in piglets receiving 0.06 g MSG/kg BW/day. Furthermore, protein levels for jejunal T1R1 and EAAT3 were higher (P < 0.05) in piglets receiving 1 g MSG/kg BW/day than those in the control and in piglets receiving 0.06 g MSG/kg BW/day. Collectively, these findings indicate that dietary MSG may beneficially stimulate glutamate signaling and sensing in the stomach and jejunum of young pigs, as well as their gastrointestinal function.     

Taurine prevents fat deposition and ameliorates plasma lipid profile in monosodium glutamate-obese rats

The aim of the present study was to evaluate the preventive effects of taurine (TAU) supplementation upon monosodium glutamate (MSG)-induced obesity. Rats treated during the first 5 days of life with MSG or saline were distributed into the following groups: control (CTL), CTL-treated with TAU (CTAU), MSG and MSG-supplemented with TAU (MTAU). CTAU and MTAU received 2.5% of TAU in their drinking water from 21 to 90 days of life. At the end of treatment, MSG and MTAU rats were hyperinsulinemic, glucose intolerant and insulin resistant, as judged by the HOMA index. MSG and MTAU rat islets secreted more insulin at 16.7 mM glucose compared to CTL. MSG rats also showed higher triglycerides (TG) and non-esterified fatty acids (NEFA) plasma levels, Lee Index, retroperitoneal and periepidydimal fat pads, compared with CTL, whereas plasma lipid concentrations and fat depots were lower in MTAU, compared with MSG rats. In addition, MSG rats had a higher liver TG content compared with CTL. TAU decreased liver TG content in both supplemented groups, but fat content only in MTAU rats. TAU supplementation did not change glucose homeostasis, insulin secretion and action, but reduced plasma and liver lipid levels in MSG rats.     

Effects of monosodium glutamate on lines of chickens having different juvenile exponential growth rates

MSG (4 mg/g BW) or the equivalent molar ratio of NaCl were injected subcutaneously into chicks from four populations of chickens derived from a double selection experiment [(1) low exponential growth rate (EGR) to 14 days of age (14L), (2) high EGR to 14 days of age (14H), (3) low EGR to 42 days of age (42L) and high EGR to 42 days of age (42H)]. MSG significantly influenced growth in chickens, but the absolute effect was genotype and sex dependent. Weights of abdominal fat pads were ranked among lines according to the sequence 42H, 14H, 42L and 14L. MSG significantly increased fat pad size by 51%, independent of genotype or sex. MSG significantly decreased breast weight in females and males by 7%. The higher percent fat pads and lower breast weights associated with MSG are indicative of growth due to fat accretion rather than protein deposition.     

Induction of ovarian activity and ovulation in an induced ovulator,the maned wolf (Chrysocyon brachyurus), using GnRH agonist and recombinant LH

Assisted reproductive techniques, such as ovarian manipulation and artificial insemination, are useful for enhancing genetic management of threatened wildlife maintained ex situ. In this study, we used noninvasive fecal hormone monitoring to investigate (1) the influence of pairing with a male on endocrine responses of female maned wolves (Chrysocyon brachyurus) to a GnRH agonist (deslorelin) and (2) the efficiency of recombinant LH (reLH) on ovulation induction in females housed alone. Deslorelin (2.1 mg Ovuplant) was given to females that were either paired with a male (n = 4) or housed alone (n = 7); the implant was removed 7 to 11 days postimplantation. Three of seven singleton females were injected with reLH (0.0375 mg) on the day of implant removal, whereas the remaining females (n = 4) did not receive the additional treatment. Fecal samples were collected 5 to 7 days/wk from all females starting 11 days prior to hormone insertion until at least 70 days post implant removal for a total of 11 hormone treatment cycles. Fecal estrogen and progestagen metabolites were extracted and analyzed by enzyme immunoassay. Evidence of ovulation, demonstrated by a surge of estrogen followed by a significant rise in progestagen, occurred in all paired females. Three of the four singleton females that did not receive reLH treatment exhibited no rise in progestagen after an estrogen surge. All singleton females treated with reLH exhibited a rise in fecal progestagen after injection, indicating ovulation. In conclusion, deslorelin is effective at inducing ovarian activity and ovulation in paired female maned wolves; however, exogenous reLH is needed to induce ovulation in females housed alone. The findings obtained from this study serve as a foundation for future application of artificial insemination to enhance genetic management of this threatened species ex situ.     

Testosterone propionate treatment of an XY gonadal dysgenetic chacma baboon

Behavioral studies of an XY gonadal dysgenetic chacma baboon prior to and during testosterone propionate treatment were carried out. The orchidectomized dysgenetic individual, two intact males, a castrate male, and two ovariectomized females were pair-tested with a group of eight ovariectomized stimulus females prior to and during their treatment with estradiol benzoate. Three test series were carried out. One series occurred prior to any treatment of the agonadal focal subject animals. During this series it was only the intact males who showed behavior change during their testing with the estrogen treated females. A second test series occurred after a month of daily testosterone propionate injections (1 mg/kg/day) had been given to the four agonadal subjects. During this test series the castrate male ejaculated once with one of the estrogen-treated females. All of the treated subjects showed increases in their frequency of yawning. Upon completion of this test series the androgen dosage was increased (2 mg/kg/day) and 2 weeks later a third test series was carried out. During this series the castrate male ejaculated with five of his eight estrogen-treated partners. The yawning of all the treated subjects continued. As had been the case in the second series the XY gonadal dysgenetic individual continued to behave as did the ovariectomized females. None of these animals showed any increase in any measure of male sexual behavior. This study establishes the fact that a genetic male primate deprived of in utero exposure to testicular hormones will go on to develop as a normal genetic female and will fail to exhibit increased levels of male sexual behavior during androgen treatment.     

Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors

The non-steroidal aromatase inhibitor CGS 20 267, at maximally effective doses in non-tumor bearing adult female rats, elicits endocrine effects mimicking those seen after surgical ovariectomy and thus induces a “medical” ovariectomy. We now report on studies characterizing the anti-tumor and endocrine effects of three orally active non-steroidal aromatase inhibitors, CGS 20 267, CGP 45 688 and CGP 47 645, in adult female rats bearing estrogen-dependent DMBA-induced mammary tumors. Doses ranging from 3 to 3000 μg/kg were given by gavage once daily for 6 weeks. After 6 weeks of treatment, the ED₅₀ for suppression of tumor volume was 10–30, 100 and 3–10 μg/kg for CGS 20 267, CGP 45 688 and CGP 47 645, respectively. The maximally effective dose for anti-tumor efficacy was 300, 1000 and 100 μg/kg for each of the three inhibitors, respectively. The observed potent anti-tumor efficacy was accompanied by potent endocrine effects. Thus, disruption of ovarian cyclicity (at maximal doses rats remained in constant diestrus) was observed in all animal from the 2nd or 3rd week of treatment to the end of the 6-week treatment period. Uterine weight, at the maximally effective doses for each of the three inhibitors, was suppressed to between 42 and 28% of pre-treatment levels. This suppression was similar to the suppression of uterine weight (27% of pre-treatment) seen after ovariectomy. Serum estradiol concentrations in rats treated with 300 μg/kg CGS 20 267 were significantly suppressed to 12% of pre-treatment levels and serum luteinizing hormone (LH) concentrations were elevated 3 to 4-fold over pre-treatment levels. Thus the potent anti-tumor efficacy seen with each of the three non-steroidal aromatase inhibitors was accompanied in each case by a variety of endocrine effects corresponding to those seen after ovariectomy.     

Neonatal androgens influence the social play of prepubescent rats

The results of six experiments designed to investigate the hormonal basis of the sex differences in the occurrence of social play in the rat are reported. From the time of weaning animals were housed in mixed-sex, peer groups of six, composed of some treated and some untreated animals. Observations were made of the animals in these groups each day between Days 26 and 40 of life in Experiments 1, 3–6 and between Days 31 and 40 in Experiment 2. In Experiment 1 it was found that males castrated on Day 1 of life engaged in less social play than did intact males, and did not differ from normal females. In Experiment 2, castration carried out at 23 days of age had no effects on the frequency with which males engaged in social play. In Experiment 3, it was found that neonatal ovariectomy had no effect on the frequency with which female pups engaged in social play. In Experiment 4, females treated on Days 1 and 2 of life with either 250 μg of testosterone propionate or 250 μg of dihydrotestosterone engaged in social play at rates comparable to those of normal males, whereas treatment with 5 μg of estradiol benzoate had no such effect. In Experiments 5 and 6 it was found that neither the reduction of testosterone-derived estradiol (by implants of the aromatization blocker, androst-1,4,6-triene-3,17-dione) nor that of testosterone-derived dihydrotestosterone (by implants of the 5α-reductase blocker, testosterone 17β-carboxylic acid) during the early neonatal period (Days 1 to 10 of life) changed the frequency of social play in intact males. The results of these experiments indicate that the sex difference in the social play of prepubescent rats is dependent on the neonatal exposure to testosterone or to its 5α-reduced metabolite, dihydrotestosterone. The reduction of testosterone to dihydrotestosterone, however, would not appear to be a necessary step.