The effects of ketamine anesthesia on hematological and serum biochemical values in female cynomolgus monkeys (Macaca fascicularis)

The effects of ketamine anesthesia (15 mg/kg body weight) on hematological and serum biochemical values were examined in six female cynomolgus monkeys (Macaca fascicularis) who were born in the wild. As control, another six female cynomolgus monkeys of the same origin were injected with physiological saline. The white blood cell count, total protein concentration, albumin concentration and calcium concentration decreased after the injection of ketamine, whereas the red blood cell count, hematocrit value, hemoglobin concentration, total cholesterol concentration, free cholesterol concentration, triglyceride concentration, transaminase activities (GOT, GPT) and alkaline phosphatase activity were not affected. A transient increase of the serum glucose level was observed within 10 minutes after ketamine injection. The relationship between these effects of ketamine anesthesia and serum cortisol levels measured by radioimmunoassay was discussed.     

Evidence for morphine-induced galactorrhea in male cynomolgus monkeys

We evaluated the effect of a daily injection of morphine hydrochloride on galactorrhea in male cynomolgus monkeys. Three groups of three monkeys (nine total) were used. The treatment schedule was separated into three periods: pre-treatment, treatment, and post-treatment. Each group of monkeys was subcutaneously injected daily with 1.5, 3.0, or 6.0 mg/kg (monkey weight) of morphine for 74–130 days, respectively, during the treatment period, and with saline during the pre-treatment and post-treatment periods. We then measured the prolactin (PRL) and testosterone (T) levels from weekly blood samples that were taken 20 hours after injection. No statistically significant differences in either the PRL or T level were detected throughout the treatment period. However, monkeys treated with 3.0 and 6.0 mg/kg/day showed a decrease in T level and an increase in PRL level during the early post-treatment period. Seven of the nine monkeys produced a milk-like secretion from their mammary gland (a symptom of galactorrhea) during the treatment and post-treatment periods. For several months of post-treatment period (average 6.75 months), we monitored the time-course changes in PRL and T levels in all monkeys for 10 hours after a single injection of morphine at the same dose given during the treatment period. Morphine induced a sudden increase in the PRL level (peaked within 30 minutes) and a gradual decrease in the T level (leveled off within 6.5–10 hours), and then returned to basal levels. These results indicate that morphine does not cause a long-term effect on hormonal changes and that a morphine-induced transient rise in PRL levels accompanied by a decrease in T levels can induce spontaneous galactorrhea in male cynomolgus monkeys.     

Predictors of social status in cynomolgus monkeys (Macaca fascicularis) after group formation

The purpose of the present study was to determine whether various behavioral and hormonal markers obtained in individually housed monkeys would be predictive of social rank following group housing. Body weight, serum cortisol and testosterone levels, and locomotor activity in an open-field apparatus were examined in 20 experimentally naive male cynomolgus monkeys (Macaca fascicularis) while they were individually housed. It was hypothesized that eventual subordinate monkeys would have higher cortisol levels and increased locomotor activity scores. These monkeys were then placed in social groups of four (five pens of four monkeys), and social rank was determined based on outcomes of dyadic agonistic encounters. Body weight correlated significantly with eventual social rank. In general, the heavier the monkey the higher the social rank. Locomotor activity in an open-field apparatus following administration of a low dose of cocaine (0.01 mg/kg, i.v.), which has been shown to increase CNS dopamine, correlated with eventual social rank such that individually housed monkeys with high levels of locomotion were more likely to become subordinate. Serum cortisol and testosterone levels failed to correlate with eventual social rank. Hypothalamic-pituitary feedback sensitivity and adrenal responsiveness were examined by measuring cortisol levels after administration of dexamethasone and following ACTH challenge. Cortisol responses in these tests were not associated with eventual social rank. These results suggest that, in addition to body weight, the level of reactivity in a novel environment after administration of a low dose of cocaine is a potential trait marker for social rank. This trait is apparently not associated with hormone levels, but may involve other CNS mechanisms.     

Measurement of serum prolactin and the effect of ketamine anesthesia on serum prolactin levels in cynomolgus monkeys (Macaca fascicularis)

The effect of an anesthetic, ketamine, on the serum prolactin level was examined in wild-originating female cynomolgus monkeys (Macaca fascicularis) imported from South East Asia. Serum prolactin levels were measured by the homologous radioimmunoassay system which was developed for human prolactin. The validity was confirmed by using an extract of pituitary gland from a female cynomolgus monkey as well as serum and amniotic fluid from a pregnant monkey. Additionally, serum luteinizing hormone (LH) levels were determined by the radioreceptor assay system developed in our laboratory using Leydig cells collected from rat's testes as a receptor fraction. The experiment was repeated three times at one-month interval, using twenty animals that were divided into three groups consisting of 5, 7 and 8 monkeys each. In the first experiment, the first group was injected with physiological saline and the second and third groups were intramuscularly given ketamine at a dose level of 5 mg/kg B.W. and 15 mg/kg B.W., respectively. In the second experiment, the first and second groups were given ketamine at a dose of 5 mg/kg B.W. and of 15 mg/kg B.W., respectively, and the third group was served as control injected with saline. In the third experiment, the first and third groups were administered with 15 mg/kg and 5 mg/kg of ketamine and the second group was injected with saline. In short, all of the twenty monkeys received the three different treatments for two months. The serum prolactin level showed a marked increase after the administration of ketamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of N-methyl-D-aspartate receptor stimulation on growth hormone secretion at specific stages of postnatal development of the male rhesus monkey

The present study attempts to examine the role of N-methyl-D-aspartate (NMDA) receptor in the central regulation of growth hormone (GH) secretion during specific stages of pubertal development of the male rhesus monkey (Macaca mulatta). Infantile (n=4), prepubertal (n=5), peripubertal (n=5) and adult (n=5) intact male rhesus monkeys were given an agonist of NMDA receptor, N-methyl-D,L-aspartate (NMA) (15 mg/kg BW) through a teflon cannula implanted in the saphenous vein. Blood samples were collected 20-60 min before and 40-80 min after the injection of the drug at 10-20 min intervals. NMA was dissolved in normal saline immediately before use and passed through a 0.22 microm filter at the time of injection. All bleedings were carried out under ketamine hydrochloride anesthesia (initial dose 5 mg/kg BW, im followed by 2.5 mg/kg at 30 min intervals). The plasma levels of GH and testosterone (T) were determined by using specific assay systems. The hypothalamic-somatotrope activity under basal conditions was studied by averaging all the GH concentrations obtained before NMA injection, whereas the sensitivity of NMDA receptor to NMA stimulation was determined by comparing basal GH levels immediately before NMA injection at 0 min and GH concentrations obtained 10 min after the injection. The mean basal plasma concentrations of GH in the four groups of animals showed marked age-related differences. The levels of GH were found to be higher in infantile and peripubertal monkeys as compared to those of prepubertal and adult animals. A single iv injection of NMA produced differential effects on GH secretion during specific stages of postnatal development depending upon the level of GH secretion under basal conditions. Whereas NMA had no demonstrable effect on GH secretion in infantile and peripubertal animals in which the basal GH levels were high, it produced pronounced effects on GH secretion in prepubertal and adult monkeys wherein baseline GH concentrations were low. In conclusion, the present study suggests that the glutamatergic component of the control system that governs GH secretion by utilizing NMDA receptor may participate in regulation of age-related changes in the secretion of GH in the male rhesus monkey.     

四种麻醉药物对食蟹猴麻醉效果分析和选择应用

目的分析比对速眠新、氯胺酮、异氟烷和利多卡因4种不同麻醉药对食蟹猴的麻醉效果。方法总结实际工作中分别使用四种不同麻醉药物对食蟹猴作用的麻醉特点。结果速眠新、氯胺酮、异氟烷均能获得较好的麻醉效果,能满足不同手术、采样需要;局麻药利多卡因对食蟹猴麻醉的实际应用不理想。结论食蟹猴的手术及其他侵犯性操作等都应该考虑生物安全和动物福利要求,实行麻醉,但应根据食蟹猴实验内容要求和不同麻醉药特点选择合适的麻醉方法,确保人员和动物安全,实验结果不受影响。     

Development of the hormonal reaction to stress in the ontogenesis of the baboon Papio hamadryas

The hormonal reaction of adrenal and gonadal glands of baboons at various ages was studied under 2 hr immobilization stress condition. Concentrations of cortisol, 11-deoxycortisol, 17-hydroxypregnenolone, dehydroepiandrosterone and testosterone were determined by radioimmunoassay in the monkey blood plasma at different times during the stress reaction. A more pronounced reaction of adrenal cortex was shown in 1 year old baboons. The peak of cortisol level in immature monkeys under stress conditions was registered much earlier than in adult monkeys.     

Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys

Surgical or pharmacologic methods to control gonadal androgen biosynthesis are effective approaches in the treatment of a variety of non-neoplastic and neoplastic diseases. For example, androgen ablation and its consequent reduction in circulating levels of testosterone is an effective therapy for advanced prostate cancers. Unfortunately, the therapeutic effectiveness of this approach is often temporary because of disease progression to the 'castration resistant' (CRPC) state, a situation for which there are limited treatment options. One mechanism thought to be responsible for the development of CRPC is extra-gonadal androgen synthesis and the resulting impact of these residual extra-gonadal androgens on prostate tumor cell proliferation. An important enzyme responsible for the synthesis of extra-gonadal androgens is CYP17A1 which possesses both 17,20-lyase and 17-hydroxylase catalytic activities with the 17,20-lyase activity being key in the androgen biosynthetic process. Orteronel (TAK-700), a novel, selective, and potent inhibitor of 17,20-lyase is under development as a drug to inhibit androgen synthesis. In this study, we quantified the inhibitory activity and specificity of orteronel for testicular and adrenal androgen production by evaluating its effects on CYP17A1 enzymatic activity, steroid production in monkey adrenal cells and human adrenal tumor cells, and serum levels of dehydroepiandrosterone (DHEA), cortisol, and testosterone after oral dosing in castrated and intact male cynomolgus monkeys. We report that orteronel potently suppresses androgen production in monkey adrenal cells but only weakly suppresses corticosterone and aldosterone production; the IC(50) value of orteronel for cortisol was ~3-fold higher than that for DHEA. After single oral dosing, serum levels of DHEA, cortisol, and testosterone were rapidly suppressed in intact cynomolgus monkeys. In castrated monkeys treated twice daily with orteronel, suppression of DHEA and testosterone persisted throughout the treatment period. In both in vivo models and in agreement with our in vitro data, suppression of serum cortisol levels following oral dosing was less than that seen for DHEA. In terms of human CYP17A1 and human adrenal tumor cells, orteronel inhibited 17,20-lyase activity 5.4 times more potently than 17-hydroxylase activity in cell-free enzyme assays and DHEA production 27 times more potently than cortisol production in human adrenal tumor cells, suggesting greater specificity of inhibition between 17,20-lyase and 17-hydroxylase activities in humans vs monkeys. In summary, orteronel potently inhibited the 17,20-lyase activity of monkey and human CYP17A1 and reduced serum androgen levels in vivo in monkeys. These findings suggest that orteronel may be an effective therapeutic option for diseases where androgen suppression is critical, such as androgen sensitive and CRPC.     

帕妥珠单抗生物类似药SMMU-27 静脉注射对食蟹猴的重复给药毒性探索研究

目的:观察帕妥珠单抗生物类似药SMMU-27四周静脉注射对食蟹猴的安全性。方法:20只健康食蟹猴按体重随机分为阳性对照组、SMMU-27低、中、高剂量组和辅料对照组,每组4只,雌雄各半。低、中、高剂量组剂量分别为15、150和450 mg/kg,阳性对照组给予150 mg/kg帕妥珠单抗(Pertuzumab),辅料对照组给予空白溶剂(0 mg/kg)。各组动物按相应体重慢速静脉注射给药,给药体积为15 m L/kg,给药速度约5 m L/min。每周给药1次,共给药4周,恢复期4周,期间进行各项毒理学指标检测。结果:一般症状结果显示给药期间与给药后,低、中、高剂量组和阳性对照组陆续有动物出现腹泻症状。高剂量组1只动物在d40时濒死剖解,其最早出现稀便,停药后腹泻状态也未见好转,生化指标显示在d28时碱性磷酸酶(Alkaline Phosphatase,ALP)升高,在d14和d40时尿素(Blood Urea,BU)升高,总蛋白(Total Protein,TP)、白蛋白(Albumin,ALB)降低。低、高剂量组和阳性对照组均有部分动物白细胞(White Blood Cell,WBC)给药后数值降低,各给药组在d14时及高剂量组和阳性对照组在d28时BU升高或有升高的趋势,恢复期时有恢复趋势。高剂量濒死动物骨髓检查发现核红细胞较多,各阶段粒细胞减少,出现较多裸核;病理检查发现肾脏可见散在多发的中度肾小管扩张,近曲小管上皮轻度变性。其余指标包括一般症状、体重、尿液、心电图、免疫学指标等未见明显与供试品相关的异常变化。结论:SMMU-27主要毒性靶部位是胃肠道(腹泻)、肾脏(血清BU升高)和血液系统(WBC下降),应与这些部位表达供试品结合的相关受体有关,属供试品的药理作用放大和延伸。因此本实验条件下食蟹猴的安全剂量(NOAEL)为150 mg/kg,致死剂量为450 mg/kg。SMMU-27与等剂量阳性对照药物毒性反应基本类似。     

Adrenal 11-hydroxylase activity in a hypercortisolemic New World primate: adaptive intra-adrenal changes

The squirrel monkey, a representative New World primate, has high plasma cortisol and aldosterone concentrations when compared to Old World primates. We measured adrenal mitochondrial 11-hydroxylase (11-OHase) activity in squirrel monkeys and in two representative Old World species (cynomolgus and rhesus macaques) in an effort to explain these elevated plasma glucocorticoid and mineralocorticoid levels. The activity of 11-OHase was 5-fold higher in the squirrel monkey than in the Old World species tested. Calculated 11-OHase Vmax was different in the squirrel monkey and the cynomolgus. However, the Km values were similar in the New World primate when compared to cynomolgus. The ability of metyrapone to block 11-OHase was less in the former than in the latter. The data are consistent with the hypothesis that the squirrel monkey adrenal cortex possesses an increased number of 11-hydroxylase enzyme units compared to that of Old World primate species, and is therefore more efficient in producing cortisol. This difference in 11-OHase activity in the squirrel monkey, in addition to other previously reported adrenal steroidogenic enzyme alterations, may be adaptive in nature, favoring increased cortisol and aldosterone production in this and possibly other New World primate species.     

Hematological and serum biochemical values in cynomolgus monkeys anesthetized with ketamine hydrochloride

The effects of ketamine anesthesia on both hematological and serum biochemical variables were investigated in 19 male and 15 female cynomolgus monkeys. Blood samples were obtained from the cephalic vein within 30 minutes of an intramuscular injection of ketamine hydrochloride (10 mg/kg). Ketamine anesthesia caused a reduction in leukocyte counts and a significant reduction in lymphocytes percentages. Ketamine anesthesia also increased the serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine phosphokinase (CPK), but reduced the serum concentrations of glucose, inorganic phosphate, sodium and potassium. The alterations of hematological and serum biochemical values will be discussed. These alterations should be considered when designing studies for and interpreting data from cynomolgus monkeys.     

Hyperprolactinemia in monkeys: Induction by an estrogen-progesterone synergy

To evaluate the synergistic effect of estrogens and progesterone on prolactin secretion, rhesus and cynomolgus monkeys in the early follicular phase received estradiol benzoate (100 μg/kg/day, sc) alone for 14 days, then in combination with progesterone (subcutaneous silastic capsule) for an additional 14 days. Blood was drawn daily by femoral venipuncture under ketamine hydrochloride anesthesia (15mg/kg). Similarly, this protocol for exogenous steroid treatment was employed in a monkey having a chronically indwelling (femoral insertion into the vena cava) cannula maintained by a vest and mobile tether apparatus; however, no anesthesia was used to obtain serum specimens. In addition, this assembly was applied to six monkeys to determine the acute effects of ketamine hydrochloride on prolactin secretion. Concentrations of prolactin, estradiol-17β, and progesterone in serum were determined by conventional radioimmunoassays. Under estrogen therapy alone, mean circulating prolactin levels declined from ~15 to < 5 ng/ml; in contrast, the addition of progesterone caused an abrupt serum prolactin elevation, ~8–12 fold. This estradiol-progesterone course led to sustained hyperprolactinemia in the chronically catheterized Monkey, whereas ketamine administration raised serum prolactin only briefly, the elevation lasting less than three hours after injection. These findings establish that an estrogen-progesterone synergy, separate from the transient effects of ketamine, Induced hyperprolactinemia in cycling monkeys having prevailing levels of estrogen and progesterone near those characteristic of late gestation, when sustained prolactin elevations are observed normally.     

Subspecies differences in hormonal and behavioral responses after group formation in squirrel monkeys

The behavioral and hormonal responses of squirrel monkeys of the Bolivian and Guyanese subspecies were compared after a group formation procedure. Two groups of each subspecies, consisting of five females and three males (later reduced to two) were observed daily during the week of group formation and for nine weeks following removal of a single male from each group. Measures of plasma cortisol were examined in the females after the initial group formation and after the groups were reduced by one male. The levels of plasma testosterone were assessed in all the males during the initial week of group formation. Linear dominance hierarchies were determined both within and across the sexes in both subspecies. The frequency and directionality of low-level aggressive interactions indicated that females of the Bolivian subspecies were dominant to the males, while the males of the Guyanese subspecies ranked over all the females. Additionally, the Bolivian squirrel monkey females showed an elevation of plasma cortisol on the day of group formation, which declined 48 hr later, then reelevated after the groups were reduced by one male and declined gradually over a nine-week period. Guyanese females showed little change in cortisol levels during both periods. This suggests fundamental hormonal, as well as behavioral, differences between the two subspecies. The change in plasma testosterone levels in the males during the initial week of group formation was positively correlated with social status. Furthermore, differences in the dynamics within individual groups for each subspecies were reflected by the levels of plasma cortisol of the female members.     

Species differences and interindividual variation in liver microsomal cytochrome P450 2A enzymes: effects on coumarin, dicumarol, and testosterone oxidation.

Antibody against purified CYP2A1 recognizes two rat liver microsomal P450 enzymes, CYP2A1 and CYP2A2, that catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone, respectively. In human liver microsomes, this antibody recognizes a single protein, namely CYP2A6, which catalyzes the 7-hydroxylation of coumarin. To examine species differences in CYP2A function, liver microsomes from nine mammalian species (rat, mouse, hamster, rabbit, guinea pig, cat, dog, cynomolgus monkey, and human) were tested for their ability to catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone and the 7-hydroxylation of coumarin. Antibody against rat CYP2A1 recognized one or more proteins in liver microsomes from all mammalian species examined. However, liver microsomes from cat, dog, cynomolgus monkey, and human catalyzed negligible rates of testosterone 7 alpha- and/or 15 alpha-hydroxylation, whereas rat and cat liver microsomes catalyzed negligible rates of coumarin 7-hydroxylation. Formation of 7-hydroxycoumarin accounted for a different proportion of the coumarin metabolites formed by liver microsomes from each of the various species examined. 7-Hydroxycoumarin was the major metabolite (greater than 70%) in human and monkey, but only a minor metabolite (less than 1%) in rat. The 7-hydroxylation of coumarin by human liver microsomes was catalyzed by a single, high-affinity enzyme (Km 0.2-0.6 microM), which was markedly inhibited (greater than 95%) by antibody against rat CYP2A1. The rate of coumarin 7-hydroxylation varied approximately 17-fold among liver microsomes from 22 human subjects. This variation was highly correlated (r2 = 0.956) with interindividual differences in the levels of CYP2A6, as determined by immunoblotting. These results indicate that CYP2A6 is largely or entirely responsible for catalyzing the 7-hydroxylation of coumarin in human liver microsomes. Treatment of monkeys with phenobarbital or dexamethasone increased coumarin 7-hydroxylase activity, whereas treatment with beta-naphthoflavone caused a slight decrease. These results suggest that environmental factors can increase or decrease CYP2A expression in cynomolgus monkeys, which implies that environmental factors may be responsible for the large variation in CYP2A6 levels in humans, although genetic factors may also be important. In contrast to rats and mice, the expression of CYP2A enzymes in cynomolgus monkeys and humans was not sexually differentiated. Despite their structural similarity to coumarin, the anticoagulants dicumarol and warfarin do not appear to be substrates for CYP2A6. The overall rate of dicumarol metabolism varied approximately 5-fold among the human liver microsomal samples, but this variation correlated poorly (r2 = 0.126) with the variation observed in CYP2A6 levels and coumarin 7-hydroxylase activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effects of different anaesthetic treatments on the adreno-cortical functions and glucose levels in NZW rabbits

The effects of five anaesthetics on the corticosterone, cortisol and glucose concentrations were investigated in the NZW rabbit. Sixty animals were assigned to 6 treatment groups (n= 10 per group): control ( iv saline solution injection), ketamine (10 mg/kg iv) with either xylazine (3 mg/kg iv) or diazepam (2 mg/kg iv), pentobarbitone (30 mg/kg iv), thiopentone (20 mg/kg iv) and fentanyl/droperidol (1 mg/kg sc). Plasma glucocorticoids were measured by competitive enzymeimmunoassay EIA and glucose by an autoanalyzer, previously validated for this species in both cases. Blood samples were obtained at 6 time-points: before injection, at 10, 30, 60, 120 min and 24 h after injection of the anaesthetics/saline. A significant decrease of plasma glucocorticoids at 10-60 min was observed in the pentobarbitone and fentanyl/ droperidol groups, whereas the administration of ketamine/diazepam or thiopentone stimulated plasma glucocorticoid release, principally in the recovery period. However, in the ketamine/xylazine group no changes were observed in the glucocorticoid levels, except for a significative increase of cortisol at 60-120 min. Glucose levels significantly increased after ketamine/diazepam administration and principally, after ketamine/xylazine treatment. The present data suggest that ketamine/xylazine has little effect on glucocorticoid levels and provides an adequate level of surgical anaesthesia, hence it would be the anaesthetic of choice, although the hyperglycaemic effect after injection has to be considered for any experimental procedures in rabbits.     

Serum hormone levels in pregnant cynomolgus monkeys

Serum levels of estradiol (E2), progesterone (P), prolactin (Prl), monkey chorionic gonadotropin (mCG), dehydroepiandrosterone sulfate (DHEAS), and cortisol (C) in pregnant cynomolgus monkeys are described. mCG, E2, and Prl patterns resembled those of pregnant rhesus monkeys. P patterns differed from data from the literature. DHEAS patterns did not follow E2 patterns. C levels did not change during pregnancy.     

Dominance, cortisol, and behavior in small groups of female cynomolgus monkeys (Macaca fascicularis)

The relationships among social rank, basal cortisol concentrations, and social behavior were assessed in adult female cynomolgus monkeys (Macaca fascicularis). Subjects were 157 unrelated, reproductively intact animals housed in 30 small groups. Rank determinations were made monthly. Blood samples were collected on two occasions, 4.5 and 7.5 months following initial group formation. Regular behavioral observations were conducted on a subset of animals over a period of 4 weeks, 9 months following group formation. Analyses revealed that serum cortisol values were significantly correlated across the two sampling periods, with no significant change in absolute values. While social rank was positively correlated across both samples, there was no relationship between rank and cortisol. However, dominant and subordinate animals did differ in the rates of performance of aggressive and submissive behaviors. These data suggest that social rank does not influence baseline serum cortisol in adult female cynomolgus monkeys, despite stability in measures of rank and cortisol and the presence of the usual behavioral differences between dominants and subordinates.     

Experimental induction of reduced ovarian reserve in a nonhuman primate model (Macaca fascicularis)

Chronic diseases including coronary heart disease and osteoporosis represent a substantial health burden to postmenopausal women, yet the initiation of these conditions and their relationships with reproductive aging remain poorly understood. This situation is due, in part, to the lack of animal models reflecting ovarian and hormonal characteristics of peri- and postmenopausal women. Ovaries of women approaching menopause are nearly depleted of primordial follicles but retain a pool of larger developing follicles and androgen-producing stroma, a condition known as reduced ovarian reserve (ROR). The long-term goal of the research presented here was to create a monkey model of reproductive aging, beginning with ROR and progressing to perimenopause and finally postmenopause. Here we sought to develop a method to reduce primordial follicles in cynomolgus monkeys (Macaca fascicularis) and document hormonal changes associated with follicle reduction or ROR. At 30 d after surgical placement of a biodegradable fiber containing approximately 200 mg of 4-vinlycyclohexene diepoxide (VCD) next to one ovary in each of 8 monkeys, primordial follicles were reduced by approximately 70%, with a corresponding decrease (83%) in antimüllerian hormone (AMH, a serum marker of ovarian follicle numbers). At 4 mo after VCD-treatment of both ovaries in 29 monkeys (approximately 200 mg VCD per ovary), AMH was reduced 56% from baseline, testosterone was unchanged, and follicular phase estradiol was slightly increased. These data indicate that VCD treatment markedly reduced primordial follicles while preserving larger estradiol- and testosterone-producing follicles and ovarian stroma, a condition that mimics ROR in women.     

Effect of nasal instillation of female urine or vaginal exudate on testosterone secretion in isolated and anesthetized male rhesus monkeys (Macaca mulatta)

Two male adult rhesus monkeys were individually placed in cages with a pulling device in order to immobilize the animals for anesthesia. The room was temperature-controlled having a light/dark period of 12/12 hours. The animals were rapidly immobilized and immediately anesthetized with ketamine i. m. (10 mg/kg of body weight). They were bled four times at 15, 30, 45, and 60 mins after the ketamine injection, twice a week during 6 weeks. When necessary, maintenance doses of ketamine were administered. The levels of serum testosterone in experimental conditions (nasal instillation of female urine or a suspension of vaginal exudate) showed significant lower values with respect to those in control conditions (saline instillation). The control levels of testosterone tend to increase up to 60 mins. The testosterone from samples obtained in experimental conditions did not show such an increase, remaining similar during the sampling and similar to the 15 min control levels that could be considered as basal. These results seem to point out some chemical information from females capable of modifying the pattern of secretion of testosterone of the males in the above mentioned experimental conditions.     

Ability of cortisol and progesterone to mediate the stimulatory effect of adrenocorticotropic hormone upon testosterone production by the porcine testis

The influence of corticosteroids and progesterone upon porcine testicular testosterone production was investigated by administration of exogenous adrenocorticotropic hormone (ACTH), cortisol and progesterone, and by applying a specific stressor. Synthetic ACTH (10 micrograms/kg BW) increased (P less than 0.01) peripheral concentrations of testosterone to peak levels of 5.58 +/- 0.74 ng/ml by 90 min but had no effect upon levels of luteinizing hormone (LH). Concentrations of corticosteroids and progesterone also increased (P less than 0.01) to peak levels of 162.26 +/- 25.61 and 8.49 +/- 1.00 ng/ml by 135 and 90 min, respectively. Exogenous cortisol (1.5 mg X three doses every 5 min) had no effect upon circulating levels of either testosterone or LH, although peripheral concentrations of corticosteroids were elevated (P less than 0.01) to peak levels of 263.57 +/- 35.03 ng/ml by 10 min after first injection. Exogenous progesterone (50 micrograms X three doses every 5 min) had no effect upon circulating levels of either testosterone or LH, although concentrations of progesterone were elevated (P less than 0.01) to peak levels of 17.17 +/- 1.5 ng/ml by 15 min after first injection. Application of an acute stressor for 5 min increased (P less than 0.05) concentrations of corticosteroids and progesterone to peak levels of 121.32 +/- 12.63 and 1.87 +/- 0.29 ng/ml by 10 and 15 min, respectively. However, concentrations of testosterone were not significantly affected (P greater than 0.10). These results indicate that the increase in testicular testosterone production which occurs in boars following ACTH administration is not mediated by either cortisol or progesterone.