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Biomedical subjects

A G Hendrickx

Publications and source records attributed to A G Hendrickx.

At least 37 records · Page 2Linked to original sources
PubMed1998

Retinoid teratogenicity in the macaque: verification of dosing regimen.

To further define teratogenicity associated with 13-cis-retinoic acid (13-cis-RA) in the cynomolgus monkey, the drug was orally administered on three different treatment regimens. Experiment (Exp.) 1 (2.5 mg/kg/day, gestational day [GD] 12-27, n = 11) investigated the teratogenicity of a single daily dose of 13-cis-RA administered shortly after embryo implantation. Pharmacokinetic sampling was done to determine retinoid profiles on the first (GD12) and last (GD27) days of treatment. Exposure to 13-cis-RA during early organogenesis in Exp. 2 (2.5 mg/kg/day, GD20-27, and 2 x 2.5 mg/kg/day, GD28-30, n = 5) investigated the potential adverse effects of 13-cis-RA on the developing limb. The use of multiple doses of 13-cis-RA in Exp. 3 (2 x 2.5 mg/kg/day, GD26-27, n = 5) investigated the necessity of double dosing on the induction of retinoid embryopathy in the macaque. Malformations of retinoid target organs as well as embryolethality were most prevalent when single daily doses of 13-cis-RA were administered during pre- and early organogenesis in Exp. 1. Moreover, multiple doses on GD26-27 failed to induce any manifestation of abnormal development in Exp. 3. These results confirm that the lowest observed adverse effect level (LOAEL) in macaques is 2.5 rather than 5.0 times greater than that observed in human pregnancies. Exposure during forelimb development (GD20-30) in Exp. 2 was unsuccessful in inducing defects of this skeletal region, although defects in several retinoid target organs (i.e., cerebellum and internal ear) were present, indicating that a teratogenic threshold was achieved. Pharmacokinetic analysis of 13-cis-RA and its metabolites on GD12 and 27 in Exp. 1 showed considerable exposure to the administered drug and its 4-oxo-metabolite. In contrast, the exposure to all-trans-RA was negligible. The results support the use of a specific treatment schedule in early gestation in the macaque as the most appropriate model for characterizing the teratogenic potential of retinoids in humans.

Abnormalities, Drug-Induced↗
PubMed1997

Effects of finasteride, a type 2 5-alpha reductase inhibitor, on fetal development in the rhesus monkey (Macaca mulatta).

In genetic male fetuses, dihydrotestosterone (DHT) plays an important role in normal prostatic and external genital differentiation. The enzyme steroid 5-alpha reductase (5 alpha R) catalyzes the conversion of testosterone (T) to DHT. The importance of 5 alpha R in sexual differentiation is evident from the study of human genetic males who congenitally lack this enzyme and consequently develop ambiguous genitalia. These individuals are specifically deficient in the type 2 isozyme, whereas the normal type 1 isozyme activity has been found. The purpose of this study was to determine 1) the suitability of the rhesus monkey for testing the safety of 5 alpha R inhibitors when administered during pregnancy and 2) the potential risk of administering a known type 2 5 alpha R inhibitor, finasteride, during the critical period of internal and external genital differentiation in rhesus monkeys. In vitro studies were also performed on selected rhesus monkey tissues to determine the distribution of the 5 alpha R isozymes. Gravid monkeys were treated once daily from gestational days (GD) 20 to 100. Sonographic monitoring was performed during the course of gestation to monitor viability, growth, and organ system development. Detailed fetal evaluations for developmental abnormalities were performed at term (GD 152 +/- 2). A group of 13 pregnant monkeys ("positive control") were given a high oral dose (2 mg/kg/day) of finasteride to demonstrate that inhibiting type 2 5 alpha R results in specific external genital abnormalities in male fetuses. Thirty-two pregnant monkeys were administered an intravenous (i.v.) formulation of finasteride at doses of 8, 80, or 800 ng/day. The highest i.v. dose selected was at least 60-750 times the semen levels of finasteride in man given orally 5 or 1 mg/day, respectively. Seventeen vehicle-control pregnant monkeys were also included. Administration of a high oral dose (2 mg/kg/day) of finasteride resulted in external genital abnormalities characterized by hypospadias, preputial adhesions to the glans, a small underdeveloped scrotum, a small penis, and a prominent midline raphe in male fetuses; however, no developmental abnormalities were seen in female fetuses. Similarly, no abnormalities were observed in either male or female fetuses of mothers given iv doses (8, 80, or 800 ng/day) of finasteride during pregnancy. The in utero sonographic findings in fetuses correlated with the gross findings at term. These studies have shown that external genital abnormalities can be produced in male monkey fetuses when exposed to a high oral dose (2 mg/kg/day) of finasteride, whereas no abnormalities were observed in fetuses exposed to the i.v. formulation of finasteride. Detailed in vitro studies demonstrated that the rhesus monkey also has two 5 alpha R isozymes (types 1 and 2) with a tissue distribution similar to that seen in man and, furthermore, that finasteride is a potent, mechanism-based inhibitor with selectivity for both human and rhesus type 2 5 alpha R. These studies have demonstrated that the monkey is a suitable model for assessing the safety of 5 alpha R inhibitors administered during pregnancy.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1997

Morphology of a six-legged goat with duplication of the intestinal, lower urinary, and genital tracts.

BACKGROUND: An adult female goat with rare malformations, which consisted of duplication of the intestinal, lower urinary, and genital tracts as well a pair of parasitic appendages, is presented. METHODS: A complete dissection was performed on a moribund female goat (Capra hircus). RESULTS: The animal had a normal body with a parasitic attachment located within the pelvic region. This attachment was represented by an ovoid, trunk-like, adipose mass that lacked internal organs or vertebrae but that had two fairly well-developed limbs with the normal components of hind limbs. There was duplication involving the external and internal genitalia, the urethra, the urinary bladder, and portions of the small intestine as well as the large bowel, including the anal openings. CONCLUSIONS: An autosite with a duplication involving the hindgut and paramesonephric anlages was identified. These features were compatible with life in utero and postutero and emanated from incomplete twinning (heteropagus twins). A review of the literature also suggests that heteropagus twins are a very rare abnormality in both domestic animals and humans.

Animals↗
PubMed1997

ELISA for the measurement of serum and urinary chorionic gonadotropin concentrations in the laboratory macaque.

A rapid, sensitive, enzyme-linked immunosorbant assay (ELISA) for the measurement of chorionic gonadotropin (CG) in serum and urine samples of laboratory macaques is reported. The ligand (CG) is captured by a readily available, widely used, and well-characterized monoclonal antibody (Mab, 518B7) generated against the beta subunit of bovine luteinizing hormone (LH). This Mab, while specific for LH, shows very little species specificity, and has been shown to detect LH and CG by radioimmunoassay (RIA) in both human and non-human primates. A polyclonal antiserum raised in rabbits against human chorionic gonadotropin (hCG) is conjugated to horseradish peroxidase, and is used as the second antibody signal. This anti-hCG antiserum cross reacts with CG secreted by both the human (hCG) and macaque (mCG). The ELISA utilizes hCG as the standard, and results are based on the relative concentrations of mCG in serum and urine. Total assay time is less than 5 hours. Range of the standard curve is 0.002 to 0.5 ng hCG/well, and the least detectable concentration of hCG is 0.0023 +/- 0.0007 ng/well. Pregnancy was detected in early pregnant macaques (M. fascicularis) on 9 (N = 1/16), 10 (N = 1/16), 11 (N = 1/16), 12 (N = 6/16), 13 (N = 1/16), 14 (N = 4/16), and 15 (N = 2/16) days following the pre-ovulatory urinary estrone conjugate peak. The detection of pregnancy by urinary mCG occurred approximately 24 to 72 hours after its detection in serum.

Animals↗
PubMed1997

Serum concentrations of oestradiol-17beta, progesterone, relaxin and chorionic gonadotrophin during blastocyst implantation in natural pregnancy cycle and in embryo transfer cycle in the rhesus monkey.

The present study was undertaken to assess the temporal association between the profiles of serum concentrations of oestradiol-17beta, progesterone, chorionic gonadotrophin (CG) and relaxin in pregnancies established naturally, and after embryo transfer, as well as in failed pregnancies in rhesus monkeys. In naturally mated cycles (group 1) a conception rate of 75% was obtained. In group 1, the mean day of CG detection in serum was 11.5 +/- 1.9 day post-ovulation, and for relaxin, 9.0 +/- 2.5 day post-ovulation. In group 2, embryo transfer to synchronous, non-mated surrogate recipients was performed; seven embryo transfer cycles yielded three pregnancies which were allowed to continue to term and normal infants were delivered. In embryo transfer cycles the mean day of CG detection was 14.8 +/- 1.8 day post-ovulation, and for relaxin, 11.4 +/- 2.6 day post-ovulation. A delay of about 3 days was observed in the appearance in circulation of CG (P < 0.05) and also of relaxin (P < 0.05) between natural mated and embryo transfer conception cycles. Significant differences (P < 0.05 for progesterone and P < 0.03 for oestradiol) were obtained for the areas under the curves for progesterone and oestradiol between days 12 and 16 in conception cycles compared with failed pregnancies. These data provide the first observation of the normal hormonal signals associated with maternal recognition of transferred embryos during the peri-implantation period, and suggest that the use of such an experimental primate embryo transfer model may help to elucidate components of maternal and embryonic signal-response mechanisms during embryo implantation.

Abortion, Veterinary↗
PubMed1997

Growth retardation in premenarchial female rhesus monkeys during chronic administration of GnRH agonist (leuprolide acetate).

Leuprolide acetate in depot form (0.75 mg/kg body weight/month, i.m.) was administered to four female rhesus monkeys from 18-30 months of age, a period that includes the premenarchial growth spurt. They were compared to eight age matched controls. As anticipated, sexual maturation was blocked in the Leuprolide group and menarche did not occur. Growth was also severely retarded; no weight gain occurred during the study in the Leuprolide group as compared to a 25% weight gain (P = .044) in the control group. The Leuprolide group also lost muscle mass. Food intake normalized for body weight was not affected. Linear growth averaged 35% less in the Leuprolide group. Serum IGF-1 concentrations increased from 486 +/- 84 to 965 +/- 47 ng/mL (P = .0025) in the Leuprolide group and from 838 +/- 139 to 3,006 +/- 545 ng/mL (P = .0016) in the control group. These data suggest that premenarchial pituitary/gonadal suppression results in a distinctive pattern of growth retardation in monkeys.

Animals↗
PubMed1997

Frequency of spontaneous congenital defects in rhesus and cynomolgus macaques.

This paper summarizes the spontaneous incidence of congenital defects in the rhesus and cynomolgus macaque colonies (Macaca mulatta and M. fascicularis) at the California Regional Primate Research Center. The computerized database used in this analysis included fetuses, term infants, juveniles, and adults that underwent a necropsy procedure over a 14-year period (1983-1996). The calculated malformation rates were 0.9% (40/4,390) and 0.3% (3/965) for the rhesus and cynomolgus monkey, respectively. Most of the observed malformations in both species affected the musculoskeletal and the cardiovascular systems, while a smaller number of defects were observed in the gastrointestinal, urogenital, endocrine, and central nervous systems. Inbreeding did not contribute to the spontaneous malformation incidence and there was no predilection for sex (male vs. female) or housing (indoors vs. outdoors) among the malformed cases. This spontaneous malformation database in our macaque colony aids in the interpretation of defects that occur in an experimental study as well as in the ongoing assessment of a healthy nonhuman primate breeding colony.

Animals↗
PubMed1997

Detection of Neospora from tissues of experimentally infected rhesus macaques by PCR and specific DNA probe hybridization.

Neospora is a newly recognized Toxoplasma-like cyst-forming coccidian parasite that causes abortion or congenital infections in naturally or experimentally infected animals. In this study, pregnant rhesus macaques were inoculated with culture-derived tachyzoites of a bovine Neospora isolate, and tissue samples from various major organs were collected from dams and fetuses for the detection of parasite DNA by using oligonucleotide primers COC-1 and COC-2 for PCR amplification of a conserved coccidial nuclear small-subunit rRNA gene sequence, and amplification products were confirmed by hybridization with a Neospora-specific DNA probe. PCR products were amplified from DNAs of different fetal monkey tissues, including brain, heart, lung, liver, spleen, skeletal muscle, skin, and placenta. In addition, Neospora DNA was amplified from the brain, heart, and lung tissues of infected rhesus macaque dams. The PCR and probe hybridization system may provide an effective method for the detection of Neospora infection in fetuses and dams from nonhuman primates and may be useful in determining the zoonotic potential of Neospora.

Animals↗
PubMed1997

Pregnancy detection by ultrasound and chorionic gonadotropin during the peri-implantation period in the macaque (Macaca fascicularis).

The goal of these studies was to correlate sonographic evidence of pregnancy during the peri-implantation period with the timing of the rise in monkey chorionic gonadotropin (mCG) as measured with an enzyme-linked immunosorbent assay. Animals were time-mated at mid-cycle, and ultrasound examinations were performed on postovulation days 12-15 (n = 77). Pregnancy was sonographically identified in 48 of 77 animals (62.3%), of which 28 had correlative ultrasound/endocrine data collected. For these animals, blood samples were obtained on postovulation days 12-15 for mCG assay. Pregnancy was identified by ultrasound on postovulation days 12 (6/28; 21.4%), 13 (6/28; 21.4%), 14 (8/28; 28.6%) or 15 (8/28; 28.6%). Seven of the 28 (25.0%) were found to have mCG levels consistent with pregnancy (> or = 1 ng/ml) on the same day as ultrasound confirmation, 12 of 28 (42.9%) were sonographically detected as pregnant 1 (n = 6), 2 (n = 3) or 3 (n = 3) days earlier than by mCG, and nine of 28 (32.1%) were found to have elevated mCG levels 1 (n = 7), 2 (n = 1) or 3 (n = 1) days earlier than ultrasound confirmation of pregnancy. The results of these studies have demonstrated (1) the utility of anatomical and endocrine techniques for detecting pregnancy approximately 3 days after the onset of implantation, and (2) the variation in the timing of implantation and the rise in circulating mCG in individual animals.

Animals↗
PubMed1996

Retinoid metabolism and transplacental pharmacokinetics in the cynomolgus monkey following a nonteratogenic dosing regimen with all-trans-retinoic acid.

Retinoids often exhibit a complex metabolic pattern and differential transplacental kinetics, which make it difficult to pinpoint the proximate compound responsible for the observed teratogenic effect. We have therefore studied the pharmacokinetics and metabolism of all-trans-retinoic acid (all-trans-RA) in cynomolgus monkeys following application of a nonteratogenic dosing regimen and compared the results with corresponding data from a previous study with a teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. All-trans-RA was administered to pregnant cynomolgus monkeys (Macaca fascicularis) by nasogastric intubation at a dose of 5 mg/kg body wt once daily from gestational day (GD) 16 to 26 and twice daily at 8-h intervals from GD 27 to 31. Examination of the fetuses of four dams on GD 100 +/- 2 showed no embryotoxic or teratogenic effects of the applied dosing regimen (Experiment 1). Maternal plasma retinoid pharmacokinetics on GD 16, 26, and 31 as well as embryonic retinoid profiles after the last drug administration on GD 31 were determined in thirteen further dams (Experiment 2). All-trans-RA reached much lower plasma concentrations after the last two treatments on GD 31 than after the first one on GD 16 and the eleventh one on GD 26 (0-24-h area-under-the-concentration-time-curve (AUC) values: 104 +/- 59 ng x h/ml (after the last treatment on GD 31), 189 +/- 110 (GD 16) and 393 +/- 305 ng x h/ml (GD 26). The predominant plasma metabolites of all-trans-RA were its beta-glucuronide and the beta-glucuronide of all-trans-4-oxo-RA. Both of these retinoids accumulated in the plasma during the period of treatment and displayed AUC values 5- to 30-fold higher than those of all-trans-RA. Embryonic concentrations of all-trans-RA were not increased over endogenous levels after the last administration on GD 31 when plasma concentrations were low. To evaluate the placental transport of all-trans-RA in the presence of high plasma concentrations, a further experiment was performed, in which a single dose of all-trans-RA (10 mg/kg body wt) was given to four pregnant monkeys on GD 31, and plasma pharmacokinetics as well as embryonic concentrations of retinoids at 4 h post-treatment were determined (Experiment 3). This dosing schedule yielded high plasma concentrations of all-trans-RA, while embryonic concentrations were about 40% of plasma levels. Based on the plasma AUC values on GDs 16 and 26 obtained in Experiment 2 and the degree of placental transfer, as determined on GD 31 in the presence of high plasma levels in Experiment 3, we estimated embryonic AUC values for the 24-h period following the nonteratogenic doses on GDs 16 and 26 in Experiment 2. These AUC values were similarly high to the embryonic AUC value of all-trans-RA obtained after application of the teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. In addition, plasma AUC values of all-trans-RA were 2- to 7-fold higher after all-trans-RA administration (present study) than after dosing with the teratogenic dose of 13-cis-RA. These results strengthen our recent suggestion that the teratogenic effects induced in cynomolgus monkeys by 13-cis-RA treatment cannot solely result from the action of all-trans-RA, but may involve 13-cis-RA and 13-cis-4-oxo-RA, which could act directly or function as transport vehicle.

Animals↗
PubMed1996

Analysis of hindbrain neural crest migration in the long-tailed monkey (Macaca fascicularis).

Neural crest cells make a substantial contribution to normal craniofacial development. Despite advances made in identifying migrating neural crest cells in avian embryos and, more recently, rodent embryos, knowledge of crest cell migration in primates has been limited to what was obtained by conventional morphological techniques. In order to determine the degree to which the nonhuman primate fits the mammalian pattern, we studied the features of putative neural crest cell migration in the hindbrain of the long-tailed monkey (Macaca fascicularis) embryo. Cranial crest cells were identified on the basis of reported distributional and morphological criteria as well as by immunocytochemical detection of the neural cell adhesion molecule (N-CAM) that labels a subpopulation of these cells. The persistent labeling of a sufficient number of crest cells with antibodies to N-CAM following their exit from the rostral, pre-otic and post-otic regions of the hindbrain facilitated tracking them along subectodermal pathways to their respective destinations in the first, second and third pharyngeal arches. Peroxidase immunocytochemistry was also employed to localize laminin and collagen-IV in neuroepithelial basement membranes. At stage 10 (8-11 somites), crest emigration occurred in areas of unfused neural folds through focal disruptions in the neuroepithelial basement membrane in both the rostral and pre-otic regions, although there was little evidence of crest migration in the post-otic hindbrain. By stage 11 (16-17 somites), the neural folds were fused (pre- and post-otic hindbrain) or in the process of fusing (rostral hindbrain), yet crest cell emigration was apparent in all three areas through discontinuities in the basement membrane. Emigration was essentially complete at stage 12 (21 somites) as indicated by nearly continuous cranial neural tube basement membranes. At this stage the pre-ganglia (trigeminal, facioacoustic and glossopharyngeal) were consistently stained with N-CAM. The current study has provided new information on mammalian neural crest in a well-established experimental model for normal and abnormal human development, including its use as a model for the retinoic acid syndrome. In this regard, the current results provide the basis for probing the mechanisms of retinoid embryopathy which may involve perturbation of hindbrain neural crest development.

Age Factors↗
PubMed1996

Effects of two antiprogestins on early pregnancy in the long-tailed macaque (Macaca fascicularis).

The abortifacient effects of mifepristone and HRP 2000 were compared in gravid long-tailed macaques. Thirty-six animals were studied with treatment administered either by the oral (0.5 or 5.0 mg/kg; N = 5 per antiprogestin per dose) or intramuscular (i.m.) routes (0.5 mg/kg; N = 5 per antiprogestin) on gestational days (GD) 23-26; six vehicle controls were included. Blood samples were collected for assay of progesterone (P4) and each of the antiprogestins (pre-treatment, daily GD 23-28, every other day GD 30-40), and animals were monitored sonographically throughout gestation. Results of these studies indicated high rates of abortion with i.m. administration (3/5 mifepristone, 4/5 HRP 2000) and 5.0 mg/kg oral route (4/5, 2/5, respectively), with less effects noted at oral doses of 0.5 mg/kg (2/5, 0/5, respectively). No early abortions were observed in the control groups. Following daily i.m. treatment, peak levels of 8-16 ng/ml mifepristone were detected whereas 6-10 ng/ ml of HRP 2000 were noted (GD 26-27). No serum levels of mifepristone were detected following either of the oral doses whereas serum levels of 2-6 ng/ml HRP 2000 were noted with high dose oral administratation. Results of these studies suggest: (1) both antiprogestins are roughly comparable in terminating early pregnancy although HRP 2000 may be more efficacious when administered i.m. whereas mifepristone may be more effective when administered orally; (2) similar levels of biological activity are seen with the i.m. and high dose oral dosing regimens, with little or no activity with the oral low dose; and (3) infants resulting from surviving pregnancies were not affected by early gestation exposure.

Abortifacient Agents, Steroidal↗
PubMed1996

Intracellular pH monkey embryos at various stages of organogenesis estimated by dimethadione distribution.

Previous experiments using the transplacental distribution of 14C-DMO (5,5-dimethyloxazolidine-2,4-dione or commonly known as dimethadione) have demonstrated that the pH of rat embryos and fluids progressively decreases during organogenesis. The aim of the present experiments was to similarly evaluate pH changes during organogenesis in the cynomolgus monkey, which is a model for human embryogenesis. Using DMO quantitated by gas chromatography-mass spectrometry as opposed to the counting of radiolabelled compound, cynomolgus monkey embryos were determined to undergo a similar decrease in embryonic pHi over an approximately comparable period of development (Days 24-36 of gestation). The ratio of DMO in chorionic fluid to DMO in maternal plasma in the cynomolgus monkey also displayed a decrease with advancing gestational age indicative of a pH decrease. The DMO transplacental distribution was found to be significantly slower in the cynomolgus monkey than that in rodents. The present investigation indicates that the magnitude of the reduction of pH in embryonic cells and in extra-embryonic fluids over a period of organogenesis in the cynomolgus monkey is similar to the reduction detected in rodent embryos and fluids over a comparable developmental period, but the relative gradient between maternal blood pH and embryonic intracellular pH is different. The difference in the pH gradient between the two species may lead to differential transplacental distribution of exogenous and endogenous substances.

Analysis of Variance↗
PubMed1996

Adolescent growth and maturation in zinc-deprived rhesus monkeys [see comment].

Growth retardation has been associated with zinc deficiency in adolescent human populations, but animal models were not available previously to explore this syndrome. Moderate dietary zinc deprivation (2 micrograms Zn/g diet) was introduced in female rhesus monkeys (Macaca mulatta; n = 10) from the beginning of puberty through menarche. Subgroups of animals (n = 4) continued to be fed the zinc-deficient diet through 45 mo of age (sexual maturity). Reduced weight gain and linear growth and lower plasma zinc concentrations (11.8 +/- 0.6 and 9.2 +/- 0.8 mumol/L in control and zinc-deficient monkeys, respectively) were evident during the premenarcheal growth spurt. Slower skeletal growth, maturation, and mineralization were recorded in the postmenarcheal period and some indicators of sexual maturation were delayed. Food intake was slightly higher in the zinc-deficient group than in controls. These data confirm that adolescent growth and maturation are vulnerable to disruption by moderate dietary zinc deprivation in nonhuman primates.

Aging↗
PubMed1996

Activity and attention in zinc-deprived adolescent monkeys.

Lethargy is characteristic of malnourished populations, but little is known about the biologic mechanism or consequences for cognitive performance. In the current experiment, 24-h activity patterns and performance of an attention task were studied in adolescent female monkeys (18-33 mo of age, n = 10/group) under conditions of moderate dietary zinc deprivation (2 micrograms Zn/g diet) and adequate dietary zinc (50 micrograms Zn/g). There were progressive decreases in daytime activity levels in the zinc-deprived group followed by slowing of growth around the time of the growth spurt. Attention performance was also impaired before the onset of growth retardation. Zinc-deprived monkeys failed to show the shift to later initiation of the rest phase of the diurnal cycle seen in controls in late adolescence. These data support previous findings that activity and attention can be affected during early stages of zinc deprivation before the onset of growth retardation.

Aging↗
PubMed1996

Effect of single-dose, early luteal phase administration of mifepristone (RU486) on implantation stage endometrium in the rhesus monkey.

The characteristics of implantation stage endometrium following a single-dose, early luteal phase application of mifepristone (RU486) in proven conception cycles has been examined in the rhesus monkey in an attempt to understand the physiological basis of the anti-implantation activity of the drug. Endometrial samples were collected from monkeys subjected to vehicle (group 1, n = 14) and RU486 (2 mg/kg body weight; group 2, n = 12) on day 2 after the presumed day of ovulation of successfully mated cycles. The average diameter of glands (P < 0.05), number of vacuolated cells (P < 0.01), number of supranuclear vacuolated cells (P < 0.05) in glandular epithelium and amount of glandular secretion (P < 0.05) were significantly lower in RU486-treated endometrium compared with control tissue samples. Additionally, 18% of glandular epithelial cells showed apoptotic and degenerative features in RU486-treated tissue samples. These data, together with the observed significant decreases in precipitate area (P < 0.02) and in the optical absorbance of alkaline phosphatase reaction end-product (P < 0.05), confirm that retardation in glandular differentiation in the upper functionalis is a likely target of antiprogestin action in implantation stage endometrium. An increased frequency of mitosis in stromal cells (P < 0.05) and a greater degree of extravasation (P < 0.05) were also observed after RU486 exposure. Despite an apparent indication of constriction and regression in few RU486-exposed endometria compared with controls, morphometric analyses did not show any changes in capillary structure. Whether endometrial vasculature in progesterone-exposed uterus is a target of antiprogestin action during the peri-implantation stage remains to be determined. Further studies are required to explain the observed increase (P < 0.02) in the area of precipitate of von Willebrand (vW) factor with no change in vW factor-positive vessels, and the apparent increase in collagen IV immunostain in subepithelial and perivascular basement membrane in implantation stage endometrium after early luteal phase RU486 treatment in monkeys.

Abortifacient Agents, Steroidal↗