Estrogen metabolism as measured in blood and urine in female rhesus monkeys

In order to measure the interconversions of estrone (E1) and estradiol (E2) and their conversion to the 16 alpha-hydroxylated estrogens, 16 alpha-hydroxy estrone (16 alpha-OHE1) and estriol (E3), we infused 11 female rhesus monkeys with [3H]E2 and [14C]E1 and measured radioactivity in the blood as E1, E2 and 16 alpha-OHE1 (n = 9) and in the urine as the glucuronides of E1, E2, 16 alpha-OHE1, and E3 (n = 11). The mean conversion of E1 to E2 as measured in blood (percent of infused E1 measured in blood as E2, [rho]1.2BB) was 29.2 +/- 1.6% and as measured in the urine of the same animals, [rho]1.2BM, was 77.4 +/- 5.9%. The mean conversion of E2 to E1, [rho]2.1BB was 21.5 +/- 1.0% and as measured in urine, [rho]2.1BM was 67.7 +/- 4.6%. Thus for both estrone and estradiol only 30-35% of the interconversions occurred in pools which were in equilibrium with the blood pool of these estrogens. The remaining 65-70% occurred in a pool, probably liver, in which glucuronidation occurred immediately after conversion. The conversion ratios (the ratio of the concentration in the blood of radioactivity as 16 alpha-OHE1 to its precursor, CRPrec,16 alpha-OHE1) was 0.036 +/- 0.008 for CRE1,16 alpha-OHE1 and 0.0039 +/- 0.0010 for CRE2,16 alpha-OHE1. The percentages of administered E1 excreted in the urine as the glucuronides of E1, E2, 16 alpha-OHE1 and E3 were 20.1 +/- 1.5, 1.6 +/- 0.2, 0.96 +/- 0.20 and 0.76 +/- 0.07 respectively. The percentages of administered E2 excreted in the urine as E1, E2, 16 alpha-OHE1 and E3 were 14.4 +/- 1.0, 2.2 +/- 0.3, 0.57 +/- 0.05 and 0.68 +/- 0.11 respectively. Thus there are minor differences in the patterns of excreted metabolites of E1 and E2. Furthermore, 16 alpha-OHE1 and E3 are not major metabolites of E1 or E2 in the female rhesus monkey.     

Estrogen dynamics in the female rhesus monkey

The metabolic clearance rates (MCR) and interconversions [( rho]BB) values for estrone (E1) and estradiol (E2) in female rhesus (Macaca mulatta) monkeys on Days 9, 14, and 23 of the menstrual cycle were measured using constant infusions of [3H] estradiol and [14C] estrone. The menstrual cycles in these monkeys were reproduced by using Silastic capsules of E2 and progesterone after bilateral ovariectomy. The serum levels of E2 and progesterone were measured by radioimmunoassay and were similar to those for the intact menstrual cycle. The MCR of E2 on Day 14 (52.8 +/- 6.8 l/day/kg) was significantly greater (p less than 0.05) than that measured on Day 9 (31.1 +/- 3.6 l/day/kg) or Day 23 (35.4 +/- 2.1 l/day/kg). The MCR of E1 was also different (p less than 0.05) on Day 14 (77.6 +/- 14.9 l/day/kg) compared to the values on Days 9 and 23 (50.2 +/- 4.9 and 48.2 +/- 3.9 l/day/kg, respectively. There was no change in percentage of free E2, percentage of albumin-bound E2, or sex hormone-binding globulin levels on those 3 days of the cycle. The interconversions between E2 and E1 were not influenced by the day of the cycle. We conclude that the high levels of E2 occurring at the time of the E2 peak result in increases in the MCRs of both E2 and E1 that are not associated with changes in the pattern of protein-binding or in the activity of the 17 beta-hydroxy steroid dehydrogenase.     

Menopause in female rhesus monkeys

Fifteen female rhesus monkeys (Macaca mulatto), ranging in age from 8 to 34 years, were studied for one year to characterize the endocrine and menstrual changes associated with menopause in this species. Five monkeys were premenopausal; these younger monkeys, ages 8–11 years, menstruated and showed cyclic ovarian activity during the 12–month study period, as evidenced by menses and periodic elevations of serum estradiol (E₂) and luteinizing hormone (LH) concentrations. Four females, ages 24–26 years, were in transition to menopause. Two of these perimenopausal females menstruated and secreted E₂ and LH in a periodic fashion; the other two females showed elevated LH concentrations, consistently low E₂ levels, and no evidence of menstruation. Six females, ages 27–34 years, were clearly postmenopausal; LH concentrations were high, whereas E₂ concentrations were uniformly low. There was a significant inverse correlation between basal E₂ concentrations and age, and a significant positive correlation between age and LH concentrations across all 15 animals. Hormonal changes indicative of ovulation, when they occurred, were generally restricted to the winter and early spring months. Histological analysis of ovaries from four postmenopausal females revealed little or no evidence of active folliculogenesis. These data indicate that menopause in female rhesus monkeys does not occur until the second half of thethird decade of life. © 1995 Wiley-Liss, Inc.     

Assessment of circadian rhythms throughout the menstrual cycle of female rhesus monkeys

Reproductive cyclicity has a significant influence on the regulation of circadian rhythms in rodents. Studies have suggested that there are changes in body temperature rhythms between the follicular and luteal phases in human females. This study examined the effects of menstrual cyclicity on physiological and behavioral circadian rhythms in female rhesus monkeys (Macaca mulatta), an acknowledged biomedical model. Seven unrestrained subjects were implanted with a biotelemetry transmitter to measure body temperature and heart rate and an accelerometer was used to measure physical activity. Water was available ad libitum and drinking was measured via an electronic circuit attached to a water lixit. A video-based task system, the Psychomotor Test System, provided environmental enrichment and delivered a pelletized diet. Mean, phase, and amplitude of each rhythm were calculated. Estrogen and progesterone conjugates were assayed and quantified from daily urine samples to identify follicular and luteal phases of the menstrual cycle. Average circadian variables were then compared between these phases. Heart rate was significantly (P< or =0.05) delayed in the luteal phase. Albeit non-significant, analysis showed a trend toward decreased circadian amplitude of body temperature in the luteal phase.     

Physical activity of adult female rhesus monkeys (Macaca mulatta) across the menstrual cycle

Physical activity is an important physiological variable impacting on a number of systems in the body. In rodents and several species of domestic animals, levels of physical activity have been reported to vary across the estrous cycle; however, it is unclear whether such changes in activity occur in women and other primates across the menstrual cycle. To determine whether significant changes in activity occur over the menstrual cycle, we continuously measured physical activity in seven adult female rhesus monkeys by accelerometry over the course of one menstrual cycle. Monkeys were checked daily for menses, and daily blood samples were collected for measurement of reproductive hormones. All monkeys displayed ovulatory menstrual cycles, ranging from 23 to 31 days in length. There was a significant increase in estradiol from the early follicular phase to the day of ovulation (F(1.005,5.023) = 40.060, P = 0.001). However, there was no significant change in physical activity across the menstrual cycle (F(2,12) = 0.225, P = 0.802), with activity levels being similar in the early follicular phase, on the day of the preovulatory rise in estradiol and during the midluteal phase. Moreover, the physical activity of these monkeys was not outside the range of physical activity that we measured in 15 ovariectomized monkeys. We conclude that, in primates, physical activity does not change across the menstrual cycle and is not influenced by physiological changes in circulating estradiol. This finding will allow investigators to record physical activity in female primates without the concern of controlling for the phase of the menstrual cycle.     

Estimation of body fat in female rhesus monkeys

Measurement of height (crown–rump length), body weight, and abdominal subcutaneous fat depth, based on skinfold thickness taken from 13 female rhesus monkeys comprising two age groups were correlated with body fat values derived from tritiated water determinations of total body water. The manner with which each measure was related to percent body fat differed as a function of age of the animal. In the young, nulliparous females, crown–rump length was the single best predictor of body fat, whereas in the older, multiparous females, skinfold thickness correlated most highly with body fat. When all measurements, including the Quetelet index [(wt/ht)² × 1,000], were combined statistically and regressed against percent body fat, a significant increase in predictive ability was obtained. When each age group was considered separately, the resulting equations again reflected the agegroup biases. In addition, as an internal check on the validity of the regression equations, an additional regression analysis was performed using morphometric data from selected animals in each age group. These equations yielded accurate estimates of body fat when compared to determinations made from total body water. These analyses indicate that the predictive accuracy of morphometric data is greatly enhanced by using these measurements in concert. Furthermore, the utility of such predictions is influenced by the specific physical characteristics of the subject population.     

Seasonal modulation of luteinizing-hormone secretion in female rhesus monkeys

The seasonal restriction of ovulations in rhesus monkeys is thought to be due to enhanced estradiol (E2)-negative feedback suppression of luteinizing hormone (LH) during the spring and summer anovulatory months. This hypothesis was examined in seven ovariectomized monkeys housed in an outdoor environment and treated with various doses of E2 in a counterbalanced design during both the anovulatory season (May-Jul) and the breeding season (Sep-Nov). Subcutaneous implants of E2 produced levels that mimicked late follicular (LF-100 pg/ml) or periovulatory concentrations (PO-190 pg/ml). Analyses of twice weekly serum samples revealed that during the period of no E2 treatment (NT), basal levels of bioactive LH were significantly lower in the summer than the fall. Although treatment with both doses of E2 lowered basal LH levels during both seasons, the decrease in LH was significantly greater during the summer. Samples collected at 15-min intervals for 2 h revealed that during NT, LH pulses were significantly slower during the summer than in the fall, whereas pulse amplitude did not differ between seasons. Treatment with both doses of E2 either abolished or significantly reduced both LH pulse amplitude and frequency in the summer. In contrast, LH pulses during the fall were not affected by E2 treatment. Response to treatment with LH-releasing hormone (5 micrograms/kg i.v.) revealed that release was significantly reduced during E2 treatment in the summer. These data indicate that seasonal changes in the environment influence both nongonadal control and E2-negative feedback inhibition of LH secretion. The reduced ability of E2 to maximally suppress LH release in the fall can thus account for the seasonally delimited pattern of ovulations observed in rhesus monkeys.     

Menstrual cycle characteristics of seasonally breeding rhesus monkeys

Rhesus monkeys in seminatural environments exhibit a distinct seasonal mating cycle with conceptions restricted to the fall and winter months. In the present study, the characteristics of menstrual cycles were examined during a 1-year period in twelve rhesus monkeys in whom pregnancy was prevented. Menses occurred throughout the year, but ovulations were observed only in the fall and winter months. Menses in the spring and summer months occurred irregularly and were associated exclusively with anovulatory cycles. The total number of ovulations exhibited by these females during the breeding season ranged from two to six and was positively related to body weight, mean luteal phase progesterone (P) levels of normal cycles and social dominance rank. Ovulations with a short luteal phase were exhibited by four females (seven cycles), with the likelihood of occurrence increasing as the breeding season progressed. The incidence of abnormal cycles was predicted from the linear combination of parity, body weight and luteal phase P of normal ovulatory cycles. These results suggest that during the seasonally delimited period of ovulation, females exhibit a range in the quality and quantity of ovulations which may be predicted by certain idiosyncratic physical and behavioral traits.     

Comparative pharmacokinetics of frusemide in female rhesus monkeys, cynomolgus monkeys and baboons

1. The pharmacokinetics of frusemide have been compared in 3 non-human primate species after single intravenous dose of 3 mg/kg of the drug. 2. Peak mean plasma concentrations of frusemide were 31.6, 33.6, 43.6 micrograms/ml in the rhesus monkey, cynomolgus monkey and baboon respectively, and concentrations declined with a half-life of about 20 min. 3. There were no notable differences in the pharmacokinetic parameters estimated from either a one-compartment or two-compartment open model. 4. There were statistically significant species-related differences in clearance, half-lives and volumes of distribution adjusted for bodyweight. 5. The pharmacokinetics of frusemide in the cynomolgus monkey are closer to those in man than are those in the rhesus monkey, the baboon or other commonly used laboratory animal species.     

Changes in electrical impedance of the vaginal medium during the menstrual cycle of female rhesus monkeys (Macaca mulatta)

Changes in electrical impedance of the vaginal medium during the menstrual cycle were recorded in female Rhesus monkeys using electrical probe and were correlated with estradiol-17 beta and progesterone plasma concentrations. A gradual decrease in impedance was observed during the follicular phase, the lowest values being observed between days 12-17 of the cycle. Impedance increased again during the first third of the luteal phase until day 21. The reversal of the impedance gradient's sign was nearly concomitant with the appearance of a detectable plasma progesterone concentration. These results support the use of vaginal impedance measurements as a help for the diagnosis of the periovulatory time in the female Rhesus monkey.     

多囊卵巢综合征猕猴的生殖特性(英文)

多囊卵巢综合征(PCOS)是临床上常见的一种内分泌失调性疾病,也是造成无排卵性不孕的重要原因。对多囊卵巢综合征动物模型的研究有10余年,迄今尚未建立起较为理想的模型动物。该研究的目的在于构建猕猴多囊卵巢综合征动物模型,并分析该模型动物的一些主要生殖特性。将6只成年雌性猕猴(6～10a)平均分成2组:PCOS模型组和对照组。模型组动物的建立方法是:在月经周期的第1、3、5天,分别皮下注射丙酸睾丸酮一次,剂量为3.5mg/kg体重;接着在第7、9、11天,分别肌注人绒毛膜促性腺激素一次,剂量是350IU/kg体重;连续注射2个月经周期。对照组动物注射生理盐水。结果显示:PCOS模型组动物呈现出高血清LH和T,分别为(5.35±0.17)IU/L和(7.58±0.14)ng/mL,而且血清LH/FSH值(5.35/1.30=4.12);模型组动物血清FSH、E2和P的含量与对照组无显著差异。腹部B超扫描结果提示,模型组动物卵巢多囊化。对两组动物进行超排处理后,模型组动物卵巢呈明显的过刺激现象,模型组动物胚胎体外培养的囊胚率为23.53%,显著低于对照组(66.67%)(P<0.05),即用丙酸睾丸酮联合人绒毛膜促性腺激素,能够建立PCOS猕猴模型,该模型动物的一些主要生殖特性与人类PCOS相似。     

Reproductive performance in capture-acclimated female rhesus monkeys (Macaca mulatta)

Behavioral and physiological data were collected over a three-year period on a colony of compound-housed rhesus monkeys (Macaca mulatta) to examine endocrine influences on sexual behavior. The reproductive performance of the experimental animals was compared to controls which were not routinely handled. The groups did not differ significantly with regard to the percentage of conceptions or other parameters of reproductive biology. The demonstration that manipulations attendant to data collection did not jeopardize reproductive success has important implications for research on primate colonies which are maintained primarily for breeding purposes. Additionally, female copulatory behavior was found to be a reliable indicator of ovulation which allows for an accurate prediction of the parturition date.     

Ultrasonographic assessment of the endometrium in rhesus monkeys during the normal menstrual cycle

This study was undertaken to determine whether cyclical changes in the endometrium of the rhesus monkey could be observed by using ultrasound. Three indices of endometrial size were examined: the antero-posterior (or ventro-dorsal), longitudinal, and transverse diameters. Changes in the ultrasonic reflectivity of the endometrium were also assessed. We have attempted to correlate these endometrial parameters with the hormonal status of the animal. Ultrasonography was performed for an average of 12 consecutive days during 19 menstrual cycles. All ultrasonic recordings were normalized to the day of the estradiol (E2) peak (Day 0). We found that the reflectivity of the endometrium was dependent on the stage of the cycle: during the follicular phase, the endometrium appeared less echogenic (darker) compared to the myometrium; in the luteal phase, the endometrium was more echogenic (lighter). During the follicular phase (Days -9 to 0), there was a linear increase in the antero-posterior (p less than 0.001), longitudinal (p less than 0.05), and transverse (p less than 0.001) diameters. In the luteal phase (Days 1-15), no significant changes were observed in these diameters. An estimated endometrial volume (EEV) was obtained by the product of the antero-posterior, longitudinal, and transverse diameters. Each animal observed during the follicular phase (n = 14) exhibited a peak in the EEV, which correlated with the day of the E2 peak (p less than 0.01). From this study, we conclude that the sonographic appearance of the endometrium of the rhesus monkey reflects the cyclical changes that occur during the menstrual cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationship between aggressive behavior and menstrual cycle stage in female rhesus monkeys (Macaca mulatta)

The aggressive behavior of eight adult female rhesus monkeys, living in a captive social group, was studied prior to and during a breeding season extended by vasectomizing all the adult males in the group. Female reproductive status was ascertained by: recording all adult female-adult male copulations, detecting menstruation by vaginal swabbing, and analyzing serum progesterone levels by radioimmunoassay. Females were more aggressive during the follicular stage of their menstrual cycle than the luteal stage or during the period prior to the onset of seasonal ovarian activity. Increases in aggression were limited to increases in the milder forms of agonistic behavior, primarily threatening gestures. Although the females showed their highest rates of noncontact aggressive response categories during the follicular stage, several showed highest rates of contact aggressive response categories in the precycling period.     

The similarity principle underlying social bonding among female rhesus monkeys

Twenty adult female rhesus monkeys (Macaca mulatta) were observed over a three-year period. They lived in a mixed captive group with kinship relations known for three generations. The study's aim was to test Seyfarth's [J. theor. Biol. 65: 671-698, 1977] model of rank-related grooming and to investigate two other possible determinants of social bonding, i.e. relative age and the group's stratification into two social classes. Data on affiliation, coalitions, and social competition were collected by means of both focal observation and instantaneous time sampling. Whereas certain elements of the existing model were confirmed, its explanatory principles were not. Social competition did not result in more contact among close-ranking females (the opposite effect was found), and the relation between affiliative behavior and coalitions was more complex than predicted. Based on multivariate analyses and a comparison of theoretical models, we propose a simpler, more encompassing principle underlying interfemale attraction. According to this 'similarity principle', rhesus females establish bonds with females whom they most resemble. The similarity may concern genetical and social background, age, hierarchical position and social class. Effects of these four factors were independently demonstrated. The most successful model assumed that similarity factors influence female bonding in a cumulative fashion.     

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.     

Age- and dominance-related variation in feeding time among free-ranging female rhesus monkeys

Observations were made on the feeding behavior of 34 lactating rhesus females (Macaca mulatta) at Tughlaqabad, India. Consistent interindividual differences in feeding times were found and two sources of this variation were identified. Time spent feeding was found to decline with female age; rhesus mothers 4–6 years old spent over 40% more time feeding than did females 11–15 years of age. When the animals were divided into high- and low-status groups, dominance was also found to relate to individual feeding times; high-status females spent more time feeding that did low-status females, but this difference was evident only when the effect of female age was held constant. The age effect is probably an expression of age-related variation in nutritional requirements due to growth in the youngest subject and, perhaps, a declining basal metabolic rate in the oldest. We speculate that the comparatively weak dominance effect is due less to the aggressive interruption of feeding bouts than it is to a presumed greater vigilance on the part of subordinant mothers in monitoring their infants' whereabouts.