Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs)

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.     

Nongenomic vasodilator action of progesterone on primate coronary arteries.

In the present investigation, we test the hypothesis that progesterone can rapidly relax, via a nongenomic mechanism, persistent flow occluding, agonist-activated coronary artery (CA) vasospasm, and hyperreactive vascular muscle cell (VMC) Ca(2+) responses in ovariectomized rhesus monkeys. CA vasospasm, induced by injection of 100 microM serotonin and 1 microM U-46619 (5-HT+U; 1 ml/30 s), resulted in a decrease in CA diameter (phi) from 1.8 +/- 0.2 to 0.3 +/- 0.1 mm at the site of focal constriction. Injection of 100 ng progesterone into the CA significantly relieved the severe vasoconstriction (1.3 +/- 0.2 mm) and reestablished distal flow in 3 min; the preconstriction phi was completely restored in 8.2 +/- 2.6 min (n = 6). Similarly, cell impermeant albumin-conjugated progesterone, but not albumin-conjugated 17 beta-estradiol, decreased 5-HT+U stimulated VMC Ca(2+) responses (250 +/- 34% of basal 30 min after stimulation) back to the prestimulation level (113 +/- 17% of basal) in 25 min (half time = 7 min). The presence of a rapid vasodilator action of progesterone in the primate CA and isolated VMC suggests its benefits in hormone replacement therapy may also include nongenomic vascular relaxant actions.     

Morphology of development in the primate: Blastocyst to villous placental stage

Examination of plastic-embedded rhesus monkey and baboon blastocysts through the implantation period has provided information on normal differentiation and development. The blastocysts show many features in common with non-primate laboratory animals, including differentiation of endoderm and its extension beyond the inner cell mass prior to implantation. However, there appears to be more cell death, and more aberrations in development. Implantation involves the adherence of trophoblast to healthy uterine luminal epithelial cells, and intrusion of syncytial trophoblast between these cells, followed by lateral expansion of the site of invasion prior to penetration of the uterine epithelial basal lamina. An amnionic cavity is formed within the inner cell mass, and is preceded by establishment of cell polarity. The definitive yolk sac is formed by an aggregation of endodermal cells adjacent to the inner cell mass. The trophoblast does not give rise to mesodermal cells, but some of these cells may be formed from endoderm prior to primitive streak formation. In both rhesus monkey and baboon, syncytial trophoblast taps the maternal vascular system relatively rapidly. In the baboon in particular large blood-filled spaces elevate the implantation site from the level of the endometrium at the stage of primary and secondary villus formation.     

Interspecific interaction of the primate groups in Kibale Forest,Uganda

An ecological survey on the influence of interspecific interaction of the primates upon the distribution of their group ranges was carried out in 100 ha of the isolated forest northern outskirts of Kibale Forest in western Uganda, Africa. The study period of 105 days was from the 12th of November, 1970 to the 24th of February, 1971, including a preliminary survey of about two months. The subjects of this study are five species of primates, i.e., black and white colobus (Colobus polykomos), red colobus (Colobus badius), red tailed monkey (Cercopithecus ascanius), blue monkey (Cercopithecus mitis), and vervet monkey (Cercopithecus aethiops), which inhabited the study area. The red colobus group is thought to be the most influential of the five in the interspecific interaction.     

Hydrophobic interaction chromatography of the rabbit uterine progesterone receptor

The chromatographic behavior of the rabbit uterine progesterone receptor interaction on several different hydrophobic matrices was characterized. Receptor, prepared in 0.6 M NaCl, exhibited a progressive retardation of elution, followed by retention, on a series of alkyl agarose columns as the length of the alkyl chain [(CH2)nH-] increased (n = 0-10), reflecting the presence of hydrophobic regions on the protein. Adsorption did not occur directly at the steroid binding site of the molecule and did not require activation to the DNA-binding form. Elution could be achieved by a decrease in the ionic strength of the buffer or the addition of glycerol, resulting in partial purification of receptor. Receptor bound tightly to phenyl agarose, although elution of the receptor under mild conditions (decreasing salt gradient, increasing glycerol gradient) resulted in poor yield and only modest purification. Passage of the non-activated progesterone receptor over Reactive Blue Sepharose effectively removed albumin, presumably by a hydrophobic interaction, although receptor was not retained. In the activated form, approximately 25% of receptor was bound to Reactive Blue Sepharose, reflecting an interaction of the Cibacron Blue dye with the polynucleotide binding site of the receptor. Hydrophobic chromatography may be an important adjunct to methods for purification of the progesterone receptor.     

Role of mechanical factors in the morphology of the primate cerebral cortex

The convoluted cortex of primates is instantly recognizable in its principal morphologic features, yet puzzling in its complex finer structure. Various hypotheses have been proposed about the mechanisms of its formation. Based on the analysis of databases of quantitative architectonic and connection data for primate prefrontal cortices, we offer support for the hypothesis that tension exerted by corticocortical connections is a significant factor in shaping the cerebral cortical landscape. Moreover, forces generated by cortical folding influence laminar morphology, and appear to have a previously unsuspected impact on cellular migration during cortical development. The evidence for a significant role of mechanical factors in cortical morphology opens the possibility of constructing computational models of cortical develoment based on physical principles. Such models are particularly relevant for understanding the relationship of cortical morphology to the connectivity of normal brains, and structurally altered brains in diseases of developmental origin, such as schizophrenia and autism.     

Role of the primate placenta in cortisol secretion by the maternal adrenals

Peripheral serum cortisol levels were measured throughout gestation in 5 intact pregnant rhesus monkeys (Macaca mulatta) and 3 hypophysectomized-fetectomized monkeys, leaving the placentas in situ and viable. These monkeys, as well as 4 other groups used to separately control for effects of pregnancy, hypophysectomy, or fetectomy, were unilaterally (left) adrenalectomized to permit comparisons of adrenal gland weights. Circulating cortisol levels of intact pregnant monkeys tended to rise slightly with advancing gestation. However, hypophysectomy at 70 to 73 days after fertilization caused a marked decline (p < 0.01) in serum cortisol concentrations to about 1/2 the preoperative level. These monkeys were fetectomized at 107 to 114 days without further reduction in circulating cortisol levels. In hypophysectomized-fetectomized monkeys, either surgical removal of the placentas near term or abortion was followed by a rapid decrease in peripheral cortisol to undetectable concentrations. Their cortisol levels were 5 to 12 times higher in left adrenal venous effluent than in peripheral circulation on the day of placental delivery. The presence of a viable placenta protected against the extensive adrenocortical involution seen in nonpregnant hypophysectomized monkeys (p < 0.01). Fetectomy, alone or in combination with hypophysectomy, did not alter left adrenal gland weights from those of intact pregnant monkeys. Thus, continued cortisol secretion and maintenance of adrenal weight in hypophysectomized-fetectomized monkeys, in the presence of a functional placenta, supports the existence of a placental adrenocorticotropin in this primate.     

Social structure of primate interaction networks facilitates the emergence of cooperation

Animal cooperation has puzzled biologists for a long time as its existence seems to contravene the basic notion of evolutionary biology that natural selection favours ‘selfish’ genes that promote only their own well-being. Evolutionary game theory has shown that cooperators can prosper in populations of selfish individuals if they occur in clusters, interacting more frequently with each other than with the selfish. Here we show that social networks of primates possess the necessary social structure to promote the emergence of cooperation. By simulating evolutionary dynamics of cooperative behaviour on interaction networks of 70 primate groups, we found that for most groups network reciprocity augmented the fixation probability for cooperation. The variation in the strength of this effect can be partly explained by the groups’ community modularity—a network measure for the groups’ heterogeneity. Thus, given selective update and partner choice mechanisms, network reciprocity has the potential to explain socially learned forms of cooperation in primate societies.     

Role of endogenous opiates in hypoxic ventilatory response in the newborn primate

The effects of opiate receptor antagonism by naltrexone hydrochloride on the biphasic hypoxic ventilatory response in the infant Macaca nemestrina have been investigated. Minute ventilation, tidal volume, and respiratory frequency were measured in six animals from timed gestations before and during inhalation of a hypoxic gas mixture. All studies were completed in non-rapid-eye-movement sleep. Arterial blood gases were obtained during each stimulus period. All animals demonstrated the typical biphasic ventilatory response to acute moderate-severe hypoxemia. After the administration of naltrexone hydrochloride to block opiate receptors, the animals still manifested a biphasic hypoxic response that was no different than that noted prior to drug administration. Naltrexone hydrochloride had no effect on room air resting ventilation in any of the animals. Our data suggest that endogenous opiates play no physiological role in the acute ventilatory response to moderate-severe hypoxia in the newborn subhuman primate.     

Influence of progesterone administration in early stage of development on morphometric parameters of the rat uterus

The aim of this study was to evaluate the effects of single injection of 0.5 mg progesterone in neonatal stage of development on morphometric parameters of the adult rat uterus. The results showed that there were no changes ofendometrial morphometry in respect to oestrous cycle in neonatal treated rats. Neonatal administration of progesterone decreased the myometrium thickness in oestrus and dioestrums owing to circular muscle layer, and disturbed sex steroids secretion during the oestrous cycle. These data suggest that neonatal administration progesterone reduces the endometrium sensitivity to sex steroids and produces the myometrium atrophy.     

Role of progesterone receptors during postpartum estrus in rats

We studied the role of progesterone receptor (PR) in the display of female sexual behavior during postpartum estrus in rats. Adult female rats were treated with the PR antagonist, RU486 (1.25 and 5 mg), 3 h after parturition and sexual behavior was evaluated throughout the first postpartum day. Estradiol and progesterone serum levels changed during the first 24 h postpartum. The highest estradiol and progesterone levels were found at 9 and 12 h postpartum, respectively. The predominant PR isoform in the hypothalamus and the preoptic area was PR-A during postpartum day. The content of PR-A increased at 6 h postpartum in the hypothalamus and the preoptic area, and decreased in both regions at 9 h. PR-B content only increased in the preoptic area at 12 h postpartum. The highest display of lordotic and proceptive behaviors were found at 12 h postpartum. The treatment with 1.25 and 5 mg of RU486 respectively reduced lordosis by 61% and 92% at 12 h postpartum. These results suggest that PR is essential in the display of postpartum estrus in rats.     

Regulated expression of osteopontin in the peri-implantation rabbit uterus

Blastocyst attachment to the lining of the mammalian uterus during early implantation involves the initial apposition of the trophoblast to the uterine epithelial surface. Osteopontin (OPN) is a glycoprotein component of the extracellular matrix that is secreted by the glandular epithelium of mammalian uteri at the time of implantation. This protein is recognized by several members of the integrin family and promotes cell-cell attachment and adhesion. In the present study, rabbit uteri were examined using Northern and in situ hybridization to evaluate the temporal and spatial distribution of OPN mRNA during early pregnancy. Northern blot analysis demonstrated a dramatic increase in OPN expression on Days 4-7 of pregnancy, corresponding to the rise in circulating progesterone and the time of initial embryo attachment in this species. In situ hybridization analysis revealed OPN mRNA expression on Day 6.75 of pregnancy, which was most prominent on endometrial epithelium. Using immunofluorescence, OPN protein was present on the glandular epithelium on Day 6.75 of pregnancy, but was absent on blastocysts. Further, no expression of OPN mRNA or protein was found in the nonpregnant endometrium. Induction of endometrial OPN expression was observed in unmated rabbits treated with progesterone alone and was prevented by cotreatment with the antiprogestin ZK137.316. Estradiol-17beta had no effect on OPN expression by itself, and estrogen priming was not necessary to demonstrate the stimulatory effect of progesterone. In The rabbit uterus, as in other mammalian species studied, OPN is expressed in a stage-specific manner by the endometrial glands during the peri-implantation period and is regulated by progesterone.     

Role of the nonhuman primate for research related to women's health

This overview of the current status of medical problems that affect women is related to current studies on pathophysiology and therapeutic interventions using nonhuman primates to demonstrate the utility of the primate model for the study of disease processes in women. The current medical literature on women's health is compared with the literature on nonhuman primate research. The findings reviewed in the articles of ILAR Journal Volume 45 Issue 2 of 2004 are evaluated in the context of the scope and problems associated with disease entities in women. Nonhuman primate research with known information regarding women's disease is discussed, and the utility of the animal model for the study of human disease is highlighted, based on its significant relevance due to similarities of nonhuman primate and human subjects' physiology, metabolism, and responses to therapeutic interventions. Additional advantages of the animal model include the ability to control the experimental environment and the capacity to perform chronic study procedures. These findings allow us to utilize the nonhuman primate as the most relevant model in the animal world for the study of human disease processes.     

Role of the embryonic vesicle and progesterone in embryonic loss in mares.

Characteristics of spontaneous embryonic loss in 21 mares were compared with those of 52 contemporary mares that maintained pregnancy. Embryonic losses were, in retrospect, grouped according to day of loss and length of the interovulatory interval, respectively, as follows: group 1, less than or equal to day 20 and less than or equal to 30 days (n = 10); group 2, less than or equal to day 20 and greater than 30 days (n = 3); and group 3, greater than day 20 and greater than 30 days (n = 8); ovulation was day 0. Mean diameter of the embryonic vesicle in group 1 was smaller (P less than 0.05) on days 12-18 than in the pregnancy-maintained group, but among the pregnancy-maintained group and the embryonic-loss groups, the mean individual growth rates of vesicles was similar (no significant difference). A more frequent (P less than 0.05) location of the vesicles in the uterine body on day 13 in group 1 was due to a greater proportion of small vesicles and for day 18 was due to a greater incidence of fixation failure. Luteal regression occurred at the expected time in 77% of the mares with loss sooner than day 20. Low concentration of progesterone on days 12, 15 and 18, a detected decrease in diameter of the corpus luteum on days 15 and 18, and an interovulatory interval of less than or equal to 30 days indicated that luteolysis was not prevented by the embryonic vesicle in group 1.(ABSTRACT TRUNCATED AT 250 WORDS)