Primer on medical decision analysis: Part 2--Building a tree

Observations were made on four captive breeding groups of rhesus monkeys in order to measure hormonal, behavioral, and genital changes in adolescent males during the annual mating season. Three questions were addressed with regard to possible effects of social environment upon reproductive maturation: (1) Does male agonistic rank influence adolescent development? (2) Does affiliation between adolescent males and adult females during the mating season influence the males' reproductive development? (3) Does maternal rank exert any effect upon reproductive maturation in adolescent sons? In many (but not all) cases male rank was positively correlated with circulating testosterone and testes weights during the mating season. Affiliative behavior (allogrooming and sexual interactions) between adolescents and adult females in their social groups bore no relationship to the degree of reproductive maturation in males. Mounts involving intromission were infrequent, but sons of high-ranking mothers gained significantly more intromissions than sons of lower-ranking females. Maternal rank was also found to correlate with circulating testosterone levels, testes weights, growth of the baculum (os penis), and maintenance of body weight in adolescent sons during the mating season. By contrast, levels of beta-endorphin in the cerebrospinal fluid of adolescent males did not correlate with social rank, testosterone levels, or genital development. These findings point to possible effects of maternal rank, as well as intermale agonistic rank, in determining reproductive maturation during adolescence in the male rhesus monkey.     

Seasonal testicular function in male rhesus monkeys

Some studies report seasonal patterns of testicular function in male rhesus monkeys even when they are housed away from females, while others suggest that exposure to sexually active females is essential for male seasonality. We conducted the present experiment (1) to test claims that seasonal testicular activation occurs in the absence of females and (2) to determine whether regular exposure to and copulation with females enhances, or is without effect upon, seasonal increases in testicular function. We studied two groups of male monkeys housed in a colony room containing no females. Males in the Female Exposure group (n = 7) were paired twice weekly with estradiol-implanted females and copulated vigorously. Males in the second group (n = 7) were placed in the same test chamber (at least 16 h after it had been scrubbed with disinfectant) but were never exposed to females. Serum testosterone levels and testis volume were monitored for both groups. Each group displayed a seasonal pattern of testosterone and of testis volume comparable in timing and magnitude to seasonal increases previously reported in group-housed males, but the two groups did not differ from each other. Our findings confirm that seasonal changes in testosterone and testis size occur in the absence of sexual interaction and demonstrate that moderate levels of sexual activity do not enhance this response.     

Age-sex differences in the expression of agonistic behavior in rhesus monkey (Macaca mulatta) groups.

Analyzed the distribution of agonistic responses (ARs) among age–sex (AS) classes of rhesus monkeys to test the hypothesis that AS differences in the use of ARs reduce the frequency of adult male involvement in those interactions involving biting and the more serious forms of prolonged contact. A group of between 84 and 91 monkeys in captivity was studied for 18 mo. Results show that submission was most frequent in juveniles (aged 1.5–3.5 yrs), but aggression increased steadily with age, albeit much more sharply in females. As infants (aged 0.5–2.5 yrs), males were more often involved in agonistic behavior than were females, but this sex difference reversed with age. A notable change in the frequency and forms of agonistic expression occurred in adolescent males (aged 3.5–5.5 yrs) such that, by adulthood, their participation in agonistic episodes was silent and brief and rarely involved biting. It is suggested that the high frequencies of ARs received by adolescent males account for the marked shift in adult male patterns of participation in intragroup agonistic interactions, as relative to females whose basic pattern of agonistic expression does not change with age. (58 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gonadal hormones influence the emergence of cortical function in nonhuman primates.

The role of gonadal hormones in the maturation of the orbital prefrontal cortex (ORB) was studied in normal male and female rhesus monkeys, monkeys given ORB lesions at 50 days of age, and female monkeys given androgen at different ages. Monkeys were tested on an object discrimination reversal task at 75 days of age. Gender influenced the performance of monkeys on the task during normal development and after ORB lesions. Normal males made fewer errors than did normal females. Females treated with androgen performed similarly to normal male monkeys. ORB lesions produced deficits in male monkeys and in females given androgen during late prenatal or early postnatal life, but not in normal females. These findings suggest that gonadal hormones may play an inductive role in the differentiation of higher cortical function in nonhuman primates. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of ejaculation on levels of testosterone, cortisol, and luteinizing hormone in peripheral plasma of rhesus monkeys.

In 3 experiments, the 1st 2 of which were conducted 1 yr apart, plasma levels of testosterone (T), luteinizing hormone (LH), and cortisol were measured in 10 adult male rhesus monkeys before and shortly after coitus. Mean levels of T and LH did not increase significantly after coitus or in control (no ejaculation) tests, but cortisol levels did in both cases. In 10 different males, no significant change was found in the plasma levels of T after electroejaculation; but in control tests (electric current withheld), the mean level of T was significantly lower at 80 and 140 min, but not at 50 min, after the test. According to present evidence, the effect of ejaculation on T levels differs in primate and nonprimate species. The effects on T levels produced by living with sexually receptive female rhesus monkeys may differ from those produced by intimate but brief contact with them. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex, Age, and Training Modulate Spatial Memory in the Rhesus Monkey (Macaca mulatta).

The authors tested 90 rhesus monkeys (Macaca mulatta) on a task of spatial memory, the spatial Delayed Recognition Span Test. The results showed that performance declined significantly with age, males had greater scores than females, and the rate of apparent decline with age was greater in males than in females. Both working and reference memory declined with age, but only working memory showed sex differences. The authors compared these data with that of 22 monkeys who were trained on a simpler version of the task before formal testing. Training had no effect on males but dramatically improved working memory in young females. The results confirm a male advantage in spatial working memory at a young age and confirm a greater decline with age in males than in females. It is important to note that prior training completely reverses the deficits of young females. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Consort bonding and operant behavior by female rhesus monkeys.

An operant conditioning situation was used to relate the leverpressing performance of female rhesus monkeys to different measures of social, sexual, and agonistic behavior that underlie the formation and dissolution of consort bonds. Nine females were trained to press a lever 250 times to gain access to a male partner. After access, a standard 60-min behavioral test took place (1,440 tests). Data were analyzed independently of the stage of the menstrual cycle. Eight females were tested with 2 males, and every female gained access faster with 1 male (i.e, preferred partner). For all 8 females, the preferred male was the one that spent more time grooming the female. For 5 females, the preferred partner was also the one that ejaculated more frequently. For 4 females, where agonistic interactions with males could be evaluated, the preferred male was the one that elicited fewer submissive behavioral patterns. These results indicate that the operant behavior of female rhesus monkeys is positively reinforced by social and sexual factors and negatively reinforced by agonistic interactions and may thus provide a measure of the strength of consort bonds. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavior of rhesus monkeys during artificial menstrual cycles.

Daily sc injections of estradiol, progesterone, and testosterone were given to 17 ovariectomized rhesus monkeys in amounts that imitated accurately the changing plasma levels of hormones in intact females with natural menstrual cycles. Because these cycles in ovariectomized, treated Ss were terminated by normal vaginal bleeding every 28 days and showed a midcycle gonadotropin surge, the authors termed them "artificial menstrual cycles." In dyadic mating tests, changes in the females' access times (leverpressing) for males, and in the males' ejaculatory performance, were closely similar during natural and artificial cycles, and there were well-marked behavioral rhythms. These rhythms were lost during 28-day control periods when ovariectomized Ss received injections of vehicle alone. Differences in ejaculatory performance during natural and artificial cycles could be accounted for by an order effect. It is concluded that the artificial cycle provides a valid and useful paradigm for a more detailed study of the neuroendocrine regulation of primate reproductive behavior. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Factors influencing sexual performance in male rhesus monkeys.

Describes a 5-yr retrospective study of the sexual behavior of 8 adult rhesus monkeys showing that sexual vigor declined over the years but testosterone levels in peripheral vein plasma did not. Two prospective experiments were carried out on these males during the 6th yr: (a) The 4 poorest performers were injected daily for 28 days with testosterone propionate (1 mg/kg). There was no significant increase in level of performance, and behavior was not correlated with plasma levels of testosterone either before or 24 hrs after the last hormone injection. (b) All 8 males were exposed to novel nonspecific sensory stimulation during tests of sexual behavior. Eight different adult male rhesus strangers—present in the room but not in the test cage—were used as stimuli, one for each experimental test. Sexual behavior during experimental and control tests did not differ. (44 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Social play soliciting by male and female juvenile rats: Effects of neonatal androgenization and sex of cagemates.

Investigated the behavior of male and female Long-Evans hooded rats during individual exposure to nonplayful juvenile social stimuli in a novel test of play-soliciting behavior in 2 experiments examining hormonal and experiential determinants of sex differences. In Exp I, using 36 female and 18 male Ss, neonatally androgenized females engaged in play soliciting at a level equal to that of male controls and greater than that of nonandrogenized female controls. In Exp II, 52 males and 32 females were reared in unisexual and bisexual groups in order to compare long-term sex-related social experience effects on juvenile play soliciting. Males exposed only to other young males engaged in greater play soliciting than males exposed to both sexes; females, in contrast, were unaffected by sex of cagemates. Within rearing conditions, however, males engaged in greater play soliciting than females. The combined results suggest that perinatal gonadal androgen exposure effects on social play are prepotent and contribute essentially to sex differences in the initiation of social play behavior. (21 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal androgens time neuroendocrine puberty in the sheep: effect of testosterone dose

In sheep, prenatal exposure to androgens during a critical period for sexual differentiation of the brain (30-90 days of gestation; 145 days is term) can advance the timing of puberty in females and prevent the preovulatory LH surge. The present study tests the hypothesis that in sheep, the timing of neuroendocrine sexual maturation is related to the amount of prenatal steroid exposure. In addition, we determined if different steroid requirements exist for sexual differentiation of the tonic and surge modes of gonadotropin secretion. Testosterone was administered weekly to three groups of pregnant ewes from days 30-90 of gestation at doses of 200, 80, or 32 mg/week. The resulting androgenized female lambs together with control males and females (n = 5-7/group) were gonadectomized at 3 weeks of age, and gonadal steroids were replaced with a SILASTIC brand estradiol-filled capsule. LH concentrations were measured from biweekly blood samples. Sustained increases in circulating LH were considered to reflect the initiation of neuroendocrine puberty. In male lambs, LH secretion started to increase at 8.3 +/- 0.9 weeks of age (mean +/- SEM). The two highest doses of prenatal androgen advanced the onset of neuroendocrine sexual maturation in females. In the 200 mg androgenized females, the pubertal LH rise (10.2 +/- 2.0 weeks) began about the same time as in males. In the 80 mg treatment group, LH concentrations increased at 16.2 +/- 1.5 weeks, which was later than in males, but well before that in normal females (27.1 +/- 0.7 weeks). For females treated with the lowest dose of androgen (32 mg), the pubertal LH increase (24.6 +/- 1.9 weeks) began about the same time as in normal females. To test the function of the LH surge system, LH was measured every 2 h for 60 h after an acute increase in circulating estradiol was produced by implanting additional estrogen capsules. All control females produced a surge in response to acute estradiol stimulation. LH surges did not occur in males, 200 mg androgenized females, or 80 mg androgenized females. Of six females from the 32 mg treatment group, two produced LH surges in response to the stimulatory feedback action of estradiol. We conclude that the greater the amount of prenatal testosterone, the earlier the initiation of the pubertal LH rise. Moreover, the finding that low doses of testosterone (32 mg/week) are capable of abolishing the LH surge without significantly advancing the timing of puberty supports our hypothesis that different steroid requirements exist for sexual differentiation of tonic and surge modes of LH secretion.     

Behavioural correlates of testosterone and seasonal changes of steroids in red-winged blackbirds

I studied the relationship between behaviour and plasma testosterone level (T) and the seasonal changes in T and plasma corticosterone levels (B) in male red-winged blackbirds, Agelaius phoeniceus. I measured T and B using radioimmunoassay, and on the day after taking blood, I observed each male's behaviour for 60 min. The time that males spent conspicuously perched and the number of songs were positively correlated with T, but the proportion of time spent conspicuously perched and the frequency of song were not correlated with T. The frequency of aggressive encounters, sexual chases, epaulet exposure when singing and flights within the territory were positively correlated with T, suggesting a direct role for circulating testosterone influencing male aggressive behaviour. Both T and B increased early in the breeding season, peaked when the first females were receptive, and decreased through the remainder of the breeding season. Late in the season, the presence of a receptive female caused males to have increased T. The peak in T when the first females were receptive, the positive correlation between aggression and T, and the response to a receptive female with increased T support predictions of the challenge hypothesis. T was positively correlated with B, suggesting a cost to the males of maintaining high T. When a receptive female was present on the male's territory, T was negatively correlated with date. Male red-winged blackbirds in Indiana may respond less to receptive females late in the season when benefits associated with protecting paternity and gaining extra-pair fertilizations decrease.Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.     

Differential Effects of Bremazocine on Oral Phencyclidine (PCP) Self-Administration in Male and Female Rhesus Monkeys.

Sex differences exist in many phases of drug abuse, but few studies have focused on sex differences in drug abuse treatment. In this study, the effects of bremazocine, a kappa-opioid receptor agonist, were compared in age-matched male and female rhesus monkeys self-administering orally delivered phencyclidine (PCP). Bremazocine (0.00032. 0.001, and 0.0025 mg/kg, intramuscular) was administered for 5 consecutive days. 15 min prior to daily 3-hr sessions when PCP (0.25 mg/ml) and water were available under concurrent fixed-ratio schedules. Bremazocine dose-dependently decreased PCP-maintained responding and consumption (mg/kg) in males and females, and these measures were suppressed at a lower bremazocine dose in females than in males. The percentage reduction in PCP-maintained responding and intake (mg/kg) was significantly greater in females than it was in males at the low and middle doses of bremazocine, suggesting that females may be more responsive to kappa agonist treatment than males. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of laminin on the characteristics and differentiation of neuronal cells from epidermal growth factor-responsive neuroepithelial cells

In many species, the timing of puberty is different in males and females. This does not simply reflect differences in the time course of activation of the testes and ovaries. Rather, sex differences in pubertal onset reside within brain mechanisms controlling GnRH secretion, as exemplified by studies conducted in sheep. Exposure of sheep fetuses to testicular steroids alters the timing of puberty, principally by reducing photoperiod responsiveness. This is manifest as an early increase in LH secretion in males or in females exposed experimentally to testosterone before birth. Steroids also act on non-photoperiodic mechanisms to abolish the preovulatory gonadotrophin surge. In view of these multiple organizational actions of steroids to control postnatal gonadotrophin secretion, it is becoming clear that there are many critical periods of brain development for organizing the GnRH neurosecretory system, and that these may be sensitive to different testosterone metabolites. Although GnRH neurones are not sexually dimorphic with respect to number, distribution or gross morphology, fundamental questions remain as to how steroids exert their effects at the cell through actions on GnRH afferents. Teleologically, these early sex-specific changes in mechanisms timing puberty maximize the chance that reproductive activity will ultimately be successful in each sex.     

Testosterone and persistence of social investigation in laboratory rats.

In 5 experiments 92 mature male and 44 mature female Long-Evans rats were individually exposed in their home cages to sexually immature conspecifics. A prominent sex difference was observed in duration of social investigation prior to a criterion of neglect. When pups were 5 days of age, no sex difference was observed, but when pups were 8 days of age and older, mature males consistently investigated them for significantly longer intervals than did mature females. Furthermore, intact males investigated prepuberal conspecifics for significantly longer intervals than did castrated males, castrated females, or intact females; none of the latter 3 groups differed significantly from each other. Following testosterone treatment, castrated males investigated unfamiliar, prepuberal conspecifics for a significantly longer duration than did untreated castrated control Ss. Combined results support the conclusion that gonadal testosterone effects a greater perseveration of social investigation in males. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sex differences in parasite infections: patterns and processes

Sex differences in parasite infection rates, intensities, or population patterns are common in a wide range of taxa. These differences are usually attributed to 1 of 2 causes: (1) ecological (sociological in humans); and (2) physiological, usually hormonal in origin. Examples of the first cause include differential exposure to pathogens because of sex-specific behavior or morphology. The second cause may stem from the well-documented association between testosterone and the immune system; sexually mature male vertebrates are often more susceptible to infection and carry higher parasite burdens in the field. Although many researchers favor one explanation over the other, the requisite controlled experiments to rule out confounding variables are often neglected. We suggest that sex differences in disease have evolved just as sex differences in morphology and behavior, and are the result of selection acting differently on males and females. Research has often focused on proximate mechanistic explanations for the sex difference in infection rates, but it is equally important to understand the generality of the patterns in an evolutionary context. Because males potentially gain more than females by taking risks and engaging in competition, sexual selection pressure has shaped male behavior and appearance to maximize competitive ability and attractiveness. Many of the classic male attributes such as antlers on deer are testosterone-dependent, putting males in what appears to be a cruel bind: become vulnerable to disease by developing an attractive secondary sexual ornament, or risk lowered mating success by reducing it. A variety of hypotheses have been put forward to explain why males have not circumvented this dilemma. The mating system of the host species will influence the likelihood of sex differences in parasite infection, because males in monogamous species are subject to weaker sexual selection than males in polygynous species. Whether these evolutionary generalizations apply to invertebrates, which lack testosterone, remains to be seen.     

Maternal adrenalectomy eliminates a surge of plasma dehydroepiandrosterone in the mother and attenuates the prenatal testosterone surge in the male fetus

Previous work has established a number of sex-related deficits in immune function, behavior, and endocrine responses to stress in the offspring of dams exposed to ethanol. To examine the potential role of maternal glucocorticoids as a mediator of these sexually dimorphic effects in the fetus, we examined the influence of prenatal alcohol exposure in the presence or absence of maternal glucocorticoids on fetal plasma corticosterone (CORT) production. An additional question to be addressed by these studies was whether maternal adrenalectomy could eliminate the known inhibition by ethanol of the prenatal surge of plasma testosterone in male fetuses. Pregnant dams were adrenalectomized (ADX) or sham-adrenalectomized on gestational day (G) 7 and placed on a liquid diet containing 35% ethanol-derived calories or pair-fed an isocaloric control diet throughout the experiment. On G18, G19, and G21, plasma levels of CORT, testosterone, and dehydroepiandrosterone (DHEA) were measured in male and female fetuses and their mothers. Ethanol administration consistently increased maternal plasma CORT levels but did not significantly alter CORT levels in the fetus. Maternal ADX resulted in compensatory increases in fetal CORT levels that were lower in fetuses of ADX dams on alcohol, suggesting a direct effect of ethanol on fetal pituitary-adrenal activity. There were no significant sex differences in fetal plasma CORT levels in response to any of these manipulations. A novel surge of maternal plasma DHEA was found on G19 that was absent in plasma from ADX dams. In spite of the absence of a surge on G19, plasma DHEA levels of ADX dams rose from very low levels at G18 to levels on G21 that were significantly higher than in Sham dams. A normal testosterone surge was observed in male fetuses on G18 and G19 from sham-adrenalectomized dams administered the pair-fed diet. However, this surge was greatly attenuated in males administered ethanol and also in male fetuses from ADX dams. These results reveal a direct inhibitory influence of ethanol on fetal CORT secretion as well as on the prenatal testosterone surge in males. Furthermore, these studies demonstrate the presence of a surge of DHEA in the pregnant rat. Overall, these data suggest that there is a critical adrenal factor in the rat that regulates the maternal surge of DHEA on G19 and the prenatal testosterone surge of male fetuses on G18-19.     

DNA-protein interactions in the proximal zeta-globin promoter: identification of novel CCACCC- and CCAAT-binding proteins

The present study assessed whether prenatal androgen and estrogen exposure affected adult spatial learning and hippocampal morphology. Water maze performance, the CA1 and CA3 pyramidal cell field, and the dentate gyrus-granule cell layer (DG-GCL) morphology were assessed at adulthood (70+ days of age) in males, females, androgen-treated (testosterone propionate, TP, or dihydrotestosterone propionate, DHTP) females (2-4 mg/day), estradiol benzoate (EB)-treated females (100 microgram/day), and males treated with the antiandrogen flutamide (8 mg/day). Pregnant rats were injected daily (sc) between Embryonic Day 16 and birth; all pups were delivered by cesarean section. Flutamide-treated males were castrated upon delivery, and adult castrates were used to control for activational effects. Steroid-sensitive sex differences were observed in water maze performance in favor of males. Males had larger CA1 and CA3 pyramidal cell field volumes and soma sizes than females, which were feminized with flutamide treatment. TP and EB, but not DHTP, masculinized CA1 pyramidal cell field volume and neuronal soma size; CA3 was masculinized in both TP- and DHTP-treated females, while EB was ineffective. No effects were observed in cell density, number, or DG-GCL volume or due to adult hormone levels. Thus, prenatal androgens and estrogen influence sex differences in adult spatial navigation and exert differential effects on CA1 and CA3 pyramidal cell morphology. Hence, in addition to the previously reported postnatal component, there is also a prenatal component to the critical period in which gonadal steroids organize the neural mechanisms underlying sex differences in adult spatial ability.     

Sexual variables and shock-elicited aggression.

Investigated the relationship between sex and the amount of shock-elicited aggression (SEA) in 4 experiments. Results show that (a) Sprague-Dawley males (n = 48) had higher SEA frequencies than females (n = 48), but this difference was not statistically significant; (b) Long-Evans males (n = 32) exhibited higher SEA frequencies than females (n = 32); (c) sham-operated Sprague-Dawley males (n = 35) showed higher SEA frequencies than castrated males (n = 35) but this difference was diminished by testosterone replacement in the castrated group; and (d) SEA was unrelated to free-field or stabilometer activity measurement (n = 40 male Sprague-Dawley rats). Considerable aggression occurred in all Ss, suggesting that although sexual variables affect SEA, they do not play as important a role as in other kinds of aggression. (28 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexual differentiation of play behavior in the ferret.

Three experiments examined the endocrine mechanisms responsible for sex differences in prepubertal play behavior of ferrets. In Exp I, 6 gonadally intact adolescent males exhibited higher levels of "stand-over" behavior than 6 females did in tests between 63 and 123 days of age with gonadally intact female partners of the same age. In Exp II, with 69 Ss, those Ss exposed to androgen or to ovarian steroids over Days 5–20 of postnatal life subsequently exhibited significantly higher levels of stand-over behavior in tests with females than did control females gonadectomized on Day 5 and not given steroids. None of the Ss in Exp II exhibited levels of stand-over behavior comparable to those of the gonadally intact males in Exp I. In Exp III, with 36 Ss, males gonadectomized and implanted subcutaneously with testosterone capsules on Day 70 and tested with females at 84–96 days of age exhibited levels of stand-over behavior comparable to those observed in Exp I in gonadally intact males of the same age (Weeks 12–24). Males gonadectomized on Day 70 and given no hormone at testing exhibited significantly lower levels of this behavior. Significantly lower levels were also exhibited by males gonadectomized on Day 35 and females gonadectomized on Day 70, regardless of whether they were tested with testosterone present after Day 70. Sex differences in the expression of prepubertal play behavior of ferrets apparently result from differential exposure of males and females to androgen over an extended postnatal period. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)