Potency in male rhesus monkeys: effects of continuously receptive females.

Ejaculations decreased and mount latencies increased when intact males were paired regularly over a 3.5-year period (3180 tests) with ovariectomized females made constantly receptive by daily injections of estradiol. The deterioration in potency was abruptly and completely reversed by substituting a group of new but similarly treated females for the original ones.

An annual rhythm in the battering of women.

Over 27,000 reports about women abused by their live-in male partners were provided by 23 shelter organizations in five locations in the United States. Cosinor analyses revealed statistically significant annual rhythms in the frequencies of abuse, with maxima in the summer. The rhythms were closely related to annual changes in ambient temperature in these locations, and the time of the maxima was similar to those previously reported for assaults and rapes. The findings support the hypothesis that violence by men toward women increases in summer independently of any major seasonal changes in the opportunity for contact between perpetrator and victim.

Sexual violence in the United States and the role of season.

An analysis by the cosinor method of over 50,000 rapes in 16 different locations in the United States revealed statistically significant annual rhythms in 14 locations, with maxima in the summer. Changes in numbers of rapes and assaults showed similar seasonal patterns, suggesting that rape comprised a subcategory of aggressive behavior. In contrast, there was a virtual absence of seasonal changes in numbers of murders. A close relation emerged between assaults and rapes, on the one hand, and temperature, on the other, in different geographical locations. The authors hypothesize that human violence, just like aggression in nonhuman primates, is influenced by exteroceptive environmental factors.

Colocalization of androgen receptors and mating-induced FOS immunoreactivity in neurons that project to the central tegmental field in male rats.

Bilateral lesions of the central tegmental field (CTF) in male rats virtually eliminate mating behavior. This study examined if mating-induced Fos expression (a measure of neuronal activation) and androgen receptors (AR) are colocalized in brain and spinal cord neurons which project to the CTF. Animals received unilateral injections of the retrograde tracer Fluorogold (FG) in the lateral part of the CTF (CTFl), and 10 days later were killed after ejaculating with females. Brains and spinal cords were examined for FG transport, AR-immunoreactivity (AR-ir), and Fos-immunoreactivity (Fos-ir). AR-ir and Fos-ir were visualized with fluorescence microscopy using cyanine-conjugated and fluorescein-conjugated secondary antibodies. The CTFl received projections from AR-containing neurons in forebrain structures (bed nucleus of stria terminalis, medial preoptic area, lateral and ventromedial hypothalamus), in the central amygdala and various mid- and hindbrain structures (dorsolateral tegmentum, superior and inferior colliculi, pedunculopontine nucleus), and in the lumbosacral spinal cord (lamina X). Some of the AR-containing neurons in bed nucleus of stria terminalis and in the dorsal part of the medial preoptic area with projections to the CTFl were activated by mating. Most AR-containing neurons in spinal lamina X with projections to the CTFl were also activated by mating. Information from spinal cord and pontine nuclei and from outputs descending from the forebrain may be relayed in the CTFl. Thus, as part of a network of hormone-sensitive neurons linking brain and spinal cord mechanisms for mating, the CTFl could participate in the integration of visceral and somatic information relevant for sexual behavior.

Influence of olfactory signals on the reproductive behaviour of social groups of rhesus monkeys (Macaca mulatta).

Olfactory influences are important in the control of reproductive function in many mammalian species including primates. Previous studies have shown that a mixture of volatile aliphatic acids (copulins), normally present in the vaginal secretions of rhesus monkeys, can exert a stimulatory effect on the sexual behaviour of males when pairs are tested in small cages. The present study deals with the role of these substances when tested in social groups of rhesus monkeys housed in a large testing arena, the purpose being to assess the effectiveness of olfactory signals under more nearly naturalistic conditions. Each group consisted of one male with four long-term ovariectomized females from which the male could choose. A counter-balanced experimental design was used in which each female of a testosterone-treated pair was given applications to the sexual skin of either copulins or control ether immediately before each 1-h behaviour test. After 16 tests, the procedure was repeated with the previously untreated pair in each group, and nine groups were separately studied. Testosterone was used here simply to enhance female proceptivity. The results showed that females received significantly more ejaculations (P less than 0.05), mounting attempts (P less than 0.01) and mounts (P less than 0.05) when bearing copulins than when bearing control ether. There were positive responses to copulins in 12 of the 36 males-females pairs, involving all males, and positive responses to ether in five of 36 pairs, involving four males. Copulins resulted in a change in the choice of sexual partner in five males, but there were no changes in the choice of partner with ether. Social factors, such as dominance, could override the responses to olfactory signals, and there was a significant treatment order effect, but this was eliminated by the counter-balanced design. These findings indicate a significant role for olfactory communication in mate selection in a socially living higher primate.

Environmental and endocrine factors influencing annual changes in sexual potency in primates.

PIP: A summary is presented of available data on breeding seasonality in primates. 15 female rhesus monkeys, whose Fallopian tubes had been ligated to prevent pregnancy, were paired with intact males in a laboratory in London; the timing of the annual increase (autumn) in mating activity was similar to that in India. 4 ovariectomized, estrogen-treated females were paired with intact males in a laboratory in Atlanta with strictly controlled photoperiod; the annual increase in mating activity persisted during the 1st year but in a less circumscribed rhythm than that of intact feral animals. In a sham-castrated group during the 2nd year in a fixed photoperiod, the annual increase in sexual activity virtually disappeared. A castrated, testosterone-treated group in the 2nd year of a fixed photoperiod, showed a brief increase in sexual activity at the expected time. Ovariectomized, estrogen-treated female rhesus monkeys paired with castrated, testosterone-treated males in a laboratory in London showed a seasonal increase in sexual activity at the expected time, indicating that it was not entirely dependent upon pituitary activation of the gonads.^ieng

Distribution of androgen receptor-like immunoreactivity in the brains of cynomolgus monkeys.

A polyclonal antibody, PA1, raised in a rabbit against fusion proteins containing fragments of the human prostatic androgen receptor (AR) was used to map the distribution of AR-like immunoreactivity in the brains of adult male and female cynomolgus monkeys. PA1 AR-immunoreactive (ARir) labeling occurred in the cell nuclei and, more weakly, in the cytoplasm of brain cells. The PA1 ARir labeling occurred primarily in brain regions previously shown on the basis of gonadal steroid autoradiography to contain androgen receptors. However, the distribution of PA1 ARir staining was substantially more restricted than that of autoradiographic labeling using 3H-androgens. The pattern of PA1 ARir labeling was closely similar between animals and occurred in the lateral septum, medial preoptic area, bed nucleus of stria terminalis, anterior, cortical, accessory basal and medial amygdala, several hypothalamic nuclei including the supraoptic, anterior, paraventricular, ventromedial and arcuate nuclei, and the premammillary nucleus. No significant sex differences were observed. With the exception of the supraoptic nucleus, reported not to be labeled by autoradiography, earlier autoradiographic findings and the current immunocytochemical results, although not congruent, have noteworthy similarities.

Behavior of rhesus monkeys during 28-day cycles of estrogen treatment.

Sixteen ovariectomized rhesus monkeys were paired, each with two males, during thirty-two 28-day periods during which they received one or more of the following schedules of daily injections: (a) different mixtures of estradiol benzoate, progesterone, and testosterone propionate (artificial menstrual cycles), (b) the doses of estradiol benzoate given in artificial cycles but without the other hormones (cyclic estradiol regimens), and (c) appropriate control treatments (625 one-hour behavioral tests). Hormone doses were adjusted to give plasma levels in the physiological range (335 blood samples). Measures of male sexual activity during artificial cycles and during cyclic estradiol regimens showed significant cyclic changes, but these changes were indistinguishable from each other. In four females studied in an operant conditioning paradigm, there was a midcycle dip in the times taken to obtain access to males during the cyclic estradiol regimens. The data indicated that the estrogen state of the female plays a preponderant role in determining the cyclic changes in the behavioral interactions of the pair independently of the effects of other ovarian hormones.

Medroxyprogesterone acetate and the nuclear uptake of testosterone and its metabolites by brain, pituitary gland and genital tract in male cynomolgus monkeys.

The synthetic progestin, medroxyprogesterone acetate (MPA), is used to treat male sex offenders, and it is also suppresses sexual activity in male monkeys. To examine the possibility that MPA may act as an anti-androgen in the primate brain, 4 intact male cynomolgus monkeys were given MPA (40 mg i.m.) once a week for 16 weeks, while 4 control males received i.m. injections of vehicle. All males were then castrated and 3 days later were given 3 mCi [3H]testosterone ([3H]T) i.v.; 1 h after injection males were killed, and radioactivity in nuclear pellets obtained from the hypothalamus (HYP), preoptic area (POA), amygdala (AMG), septum, pituitary gland and genital tract was analyzed by HPLC. Concentrations of [3H]T and [3H]dihydrotestosterone in nuclear pellets were 65-96% lower in MPA-treated males than in controls (P less than 0.001), but the aromatized metabolite, [3H]estradiol, which was the major form of radioactivity present in nuclear pellets from HYP, POA and AMG, was unchanged. There were no differences in concentrations of [3H]T in supernatants from the tissues of MPA-treated and control males. Because the reduced nuclear uptake of androgen in brain occurred in males whose androgen-dependent behavior had been suppressed by MPA treatments, it is proposed that MPA may have anti-androgenic effects at the level of the cell nucleus in brain regions that control behavior.

The interaction of testosterone with the brain of the orchidectomized primate fetus.

At certain times during gestation, the testes of the fetal macaque produce plasma levels of testosterone (T) that are similar to those of adults. It is thought that testosterone acts on the brain via estrogen and androgen receptors to organize the development of sexually dimorphic neural structures that underlie sex differences in behavior. To test the proposition that there are male-female differences in the occupation of steroid receptor binding sites during fetal development in the cynomolgus macaque, we have compared the uptake of [3H]T and its metabolites in: (1) 5 intact males (plasma T 571.2 +/- 215.5 ng/100 ml); (2) 5 intact females (33.8 +/- 25.2 ng/100 ml); (3) in 5 males orchidectomized in utero (14.6 +/- 5.7 ng/100 ml). About 1 week after fetal gonadectomy or sham-operation, all fetuses were given 500 microCi [3H]T s.c. and were then delivered 60 min later by Cesarean section. Brains were removed and dissected into blocks containing the hypothalamus and preoptic area, amygdala, hippocampus, and midbrain. Samples of cerebral and cerebellar cortex were also obtained. Purified nuclear pellets were prepared by centrifugation through 2 M sucrose and were extracted into ether and analyzed by high performance liquid chromatography. Hypothalamic nuclear concentrations of [3H]E2 in intact males (847 +/- 195 dpm per mg DNA) were significantly lower than those in sham-operated females (2147 +/- 542 dpm per mg DNA) (P less than 0.05), but those in orchidectomized males (2233 +/- 345 dpm per mg DNA) were similar to concentrations in females.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen receptor and mating-induced fos immunoreactivity are co-localized in limbic and midbrain neurons that project to the male rat medial preoptic area.

Two studies were designed to document neuronal colocalization of androgen receptor immunoreactivity and mating-induced Fos immunoreactivity (AR-ir, Fos-ir) in brain of male rats and to examine the extent to which limbic and midbrain neurons that project to the preoptic area are androgen sensitive and activated by mating. Brains from male rats, killed 1 h after ejaculating with receptive females, were examined for Fos-ir and AR-ir and compared with those from control rats not given access to females. PG21 anti-AR and anti-c-fos primary antibodies were visualized by fluorescence microscopy using cyanine-conjugated and fluorescein-conjugated secondary antibodies. In mated males (Expt. 1), Fos-ir and AR-ir were colocalized in neurons of the medial preoptic nucleus (MPN), the dorsal medial amygdala (dMEA), the central tegmental field (CTF), the bed nucleus of the stria terminalis, the anterior hypothalamus, the lateral hypothalamus, and the ventral premamillary nucleus. In Expt. 2, male rats received a unilateral injection of the retrograde tracer FluoroGold (FG) in the preoptic area and four days later were killed after ejaculating with receptive females. Brains were subsequently examined for FG transport, Fos-ir and AR-ir. Fluorogold-containing neurons were present in dMEA and CTF as well as in other hypothalamic and limbic regions known to project to the MPN. In dMEA and CTF, nuclear colocalization of AR-ir and mating-induced Fos-ir was present in a proportion of FG-containing neurons. Sexually relevant information may be carried through the brain by an interconnected network of hormone-sensitive neurons.

Combined effects of Depo-Provera and Fadrozole on the sexual behavior of intact male cynomolgus monkeys (Macaca fascicularis).

Our previous studies showed that treating castrated, testosterone-treated male cynomolgus monkeys with Depo-Provera (medroxyprogesterone acetate, MPA) decreased ejaculatory performance and also measures of male sexual motivation by about 40%. Similarly, treating castrated, testosterone-treated males with the nonsteroidal aromatase inhibitor, Fadrozole, decreased ejaculatory performance and male sexual motivation again by about 40%. These behavioral decrements are, of course, mediated by totally different mechanisms. We have therefore hypothesized that both unchanged T and E2 might be important for the control of sexual behavior in this male primate, and the present study examined the consequences of administering Fadrozole at a dose of 0.25 mg/kg/day to intact male cynomolgus monkeys being treated with 40 mg/week MPA. Intact males were each tested with an ovariectomized, E2-treated female partner (i) before treatment, (ii) during treatment with MPA alone, and (iii) during treatment with MPA and either Fadrozole or water administered SC by osmotic minipumps. As in previous studies, MPA significantly decreased plasma T levels and sexual behavior. But additional treatment with Fadrozole resulted in a rapid increase in plasma T levels although causing a further decline in sexual behavior. Results supported the view that both unchanged T and its aromatized product are important for ejaculatory activity and sexual motivation in the primate. Fadrozole's effect on plasma T may have been due to the elimination of the negative feedback of E2 on the hypothalamic-pituitary-gonadal axis.

Medroxyprogesterone acetate decreases the sexual activity of male cynomolgus monkeys (Macaca fascicularis): an action on the brain?

Medroxyprogesterone acetate (MPA), a synthetic progestin with androgen-depleting activity, is used to treat the deviant behavior of male sex offenders. In male cynomolgus monkeys, MPA reduces plasma testosterone (T) levels and sexual behavior, but the behavioral effects are clearly different from those of surgical castration. Because MPA is selectively taken up in unchanged form by the nuclei of neurons in the hypothalamus and preoptic area of male cynomolgus monkeys, and because it interferes with the uptake of T throughout the brain and pituitary gland, we have proposed that the behavioral effects of MPA may be mediated by brain mechanisms regulating sexual motivation that are relatively independent of circulating T levels. To test this hypothesis, eight castrated male cynomolgus monkeys bearing Silastic T implants SC were each observed during 60 min behavior tests with an ovariectomized, estrogen-treated female throughout three 4-week periods separated by 4-week periods without testing. After the first 4 weeks of testing, males received weekly IM injections of 40 mg MPA (six males) or vehicle (two males); the dose of MPA being equivalent on a body weight basis to those used clinically. Although plasma T was maintained in the upper range for intact males throughout the study, MPA treatment resulted in significantly decreased ejaculations and mounting attempts by weeks 5-6. These results demonstrated that the inhibitory effects of MPA on male behavior were independent of the reduction of plasma T levels, which points to a direct action on brain mechanisms controlling male sexual behavior.

Effects of medroxyprogesterone acetate on plasma testosterone and sexual behavior in male cynomolgus monkeys (Macaca fascicularis).

Medroxyprogesterone acetate (MPA), a synthetic progestin with androgen-depleting activity, is used to treat the deviant sexual behavior of men. To investigate the effects of MPA in another anthropoid primate, 16 oppositely-sexed pairs of cynomolgus monkeys were observed in one-hour behavior tests during 15 successive 4-week periods conducted before, during and after administering to males weekly IM injections of first 20 mg and then 40 mg MPA. The doses used were comparable on a body weight basis to those employed clinically. Blood samples were collected weekly and assayed for plasma testosterone. During MPA treatment both plasma testosterone and ejaculatory behavior were significantly decreased, but the changes in behavior were less marked than the changes in hormone levels. There were clear differences between individual males in the effects of treatment, and the identity and hormonal status of the female partners also influenced the results. During the 6 month withdrawal period, effects were only partially reversible, and the data suggested that the behavioral changes depended on the hormonal changes rather than the opposite. However, a direct central action of MPA on behavioral mechanisms could not be excluded.

Progesterone decreases mating and estradiol uptake in preoptic areas of male monkeys.

Synthetic progestins such as medroxyprogesterone acetate (MPA) are used widely in the treatment of male sex offenders. In male cynomolgus monkeys (Macaca fascicularis) treated with testosterone (T), both MPA and progesterone (P) had comparable inhibitory effects on male sexual motivation and behavior. To determine if P, like MPA, decreases endogenous T levels, plasma T and P levels were analyzed in weekly blood samples (N=186) from eight intact males, each paired with a sexually receptive female before, during, and after treatment with subcutaneous Silastic P implants (336 behavior tests). P treatment decreased sexual activity but not plasma T levels. To ascertain if P, like MPA, acts by decreasing the nuclear uptake of T by brain, four P-treated and four control males were euthanized 60 min after intravenous injection of 3 mCi of [3H]T. The nuclear uptake of unchanged [3H]T and its metabolites [3H]E(2) and [3H]DHT was measured in samples of brain, pituitary gland, genital tract, and liver. P, unlike MPA, did not affect the nuclear uptake of [3H]androgens by brain, but reduced by 80% the nuclear accumulation of [3H]E(2) in tissue samples containing preoptic area and the anterior part of the bed nucleus of stria terminalis, although not in samples from hypothalamus or amygdala.

Effects of progesterone on the sexual behavior of castrated, testosterone-treated male cynomolgus monkeys (Macaca fascicularis).

In male cynomolgus monkeys the synthetic progestin, medroxyprogesterone acetate (MPA), decreases testosterone (T) levels and sexual behavior, binds to progestin receptors in brain, and reduces by about 70% the uptake of [3H]androgens by both brain and genital tract tissues. To examine the behavioral effects of progesterone (P) itself, eight castrated, T-treated males were each tested twice weekly with an estrogenized female before, during, and after they were treated with two SC Silastic P implants. Data from six 4-week treatment periods were analyzed to facilitate comparisons with our previous data using MPA: i) baseline, ii) weeks 4-7 of P treatment, iii) weeks 8-11 of P treatment, iv) weeks 1-4 after P implants were removed, v) weeks 5-8 after P withdrawal, and finally vi) weeks 9-12 after P withdrawal (384 1 h behavior tests). Weekly blood samples (N = 192) were analyzed by radioimmunoassay to determine plasma levels of both T and P. P treatment, which resulted in high plasma P levels (about 44 ng/ml), produced decrements in measures of male sexual behavior and motivation that were both qualitatively and quantitatively similar to those produced by MPA treatment but, unlike MPA, P did not decrease plasma T levels or change them in any way (about 850 ng/100 ml throughout). The findings suggest that P implants may be preferable to weekly MPA injections in the treatment of male sex offenders because they require less patient compliance and may not have MPA's troubling side effects.

Comparison of the effects of testosterone and dihydrotestosterone on the behavior of male cynomolgus monkeys (Macaca fascicularis).

To compare the behavioral effects of testosterone propionate (TP) and diyhdrotestosterone propionate (DHTP) at doses producing plasma levels of androgens within the physiological rage, observations were made on 4 castrated male cynomolgus monkeys during successive 4-week treatment periods while they received 25, 50, 100, 200, 400 and 800 micrograms of either TP or DHTP SC/day in counterbalanced order. Males were tested with each of the same 4 female partners (16 pairs, 1024 1-hr behavior tests). Males were injected at 1600 hr and blood samples were obtained at 0800 hr (256 samples, 456 hormone determinations). Physiological plasma levels of T resulted from the 200 micrograms and 400 micrograms TP treatments, and were associated with significantly increased ejaculatory behavior. Physiological plasma levels of DHT resulted from the 50 micrograms and 100 micrograms DHTP treatments, but there were no changes in ejaculatory behavior over the entire DHTP dose range used. This difference in the behavioral effects of TP and DHTP, not previously reported for a primate, could not be accounted for by the effects of treatment order, season, long-term behavioral testing, female sexual motivation or behavior reflecting the peripheral action of androgens.

Effects of mating on c-fos expression in the brains of male macaques.

The c-fos polyclonal anti-c-fos antibody was used to examine the effects of mating on Fos expression in brain neurons of 11 male macaques. Behavior tests were for 30 min, five males were unmated, four were mated, and two were social controls. Mated males were killed 60 min after ejaculation. Social controls were paired with females, but mating did not occur. Fos immunoreactive (Fos-ir) neuronal nuclei were counted in nine brain regions extending from the medial preoptic to the mammillary body area of all males. In contrast to previous reports on nonprimate laboratory species, overall there was as much Fos-ir in unmated as in mated males. Moreover, there was significantly less Fos expression in four brain regions (known to contain steroid receptors), namely, ventromedial hypothalamus, arcuate nucleus, lateral mammillary area, and bed nucleus of stria terminalis, of mated than of unmated males. There were no significant differences between mated and unmated males in the 5 other brain regions studied. These findings may reflect taxonomic differences between primates and nonprimates, or result from greater neural activation in feral animals maintained in a laboratory than in domesticated, inbred laboratory species. The simplest interpretation would be that neural activity in the male primate is turned off by mating in some brain sites but not in others.

Testosterone and its metabolites in male cynomolgus monkeys (Macaca fascicularis): behavior and biochemistry.

To extend our previous study on the behavioral effects of testosterone propionate (TP) and dihydrotestosterone propionate (DHTP) to a dose-range producing supra-physiological plasma androgen levels, 4 castrated cynomolgus monkeys were tested with the same 4 females during successive 4-week treatment periods while receiving 800 micrograms, 1.6 mg, 3.2 mg, 6.4 mg and 12.8 mg of TP or DHTP SC/day in counterbalanced order (16 pairs, 828 1-hr tests). Both androgens increased male sexual activity, but DHTP was less effective than TP in increasing the numbers of ejaculations per test and failed to restore ejaculations to intact levels. Giving androgen-treated males single injections of 50 micrograms and 100 micrograms estradiol benzoate (EB) was without any additional effect on behavior (16 pairs, 256 tests). To examine hormonal effects in the brain, castrated males were given either 3H-T or 3H-DHT, and tissues were examined by high performance liquid chromatography (hplc). After 3H-T, 3H-E2 and unchanged 3H-T were the major forms of radioactivity in nuclei from hypothalamus, preoptic area and amygdala. After 3H-DHT, unchanged 3H-DHT predominated. The lower behavioral effectiveness of DHT could not be ascribed to its failure to enter the brain. The data suggested a role for unchanged T in the regulation of ejaculatory behavior in a male primate.

Behavioral responses to Depo-Provera, Fadrozole, and estradiol in castrated, testosterone-treated cynomolgus monkeys (Macaca fascicularis): the involvement of progestin receptors.

Sexual motivation and behavior decreased in male cynomolgus monkeys given either Depo-Provera (medroxyprogesterone acetate, MPA), which reduces androgen uptake by brain, or the nonsteroidal aromatase inhibitor, Fadrozole, which virtually eliminates the conversion of testosterone (T) to estradiol (E2) in brain. This suggested that both unchanged T and E2 are important for the control of male primate sexual behavior, but combined treatment with MPA and Fadrozole did not have the anticipated summatory effects in intact males: the behavioral decrements when MPA-treated males were given Fadrozole were about half those observed when Fadrozole was given alone. The present study tested the hypothesis that Fadrozole suppressed the behavioral effects of MPA by preventing the induction by E2 of progestin receptors in the brain to which MPA binds. Eight castrated, T-treated males were each tested with an estrogenized female i) during baseline, ii) during MPA treatment, iii) during treatment with MPA and Fadrozole together, and iv) with E2 treatment added to condition (iii) (256 1-h behavior tests). All dosages were those used in previous studies. Sexual motivation, as reflected in mounting attempts and mounting attempt latencies, was further diminished by E2 treatment in males receiving both MPA and Fadrozole, but ejaculatory activity was not changed. Immunocytochemistry demonstrated that the distributions of progestin and androgen receptors were little affected by MPA treatment, and that progestin receptor immunoreactivity was almost completely abolished in the brains of males receiving both MPA and Fadrozole but present in those receiving additional E2 treatment, findings that supported the hypothesis.