Human uterine leiomyomata express higher levels of peroxisome proliferator-activated receptor gamma, retinoid X receptor alpha, and all-trans retinoic acid than myometrium.

Uterine leiomyomata are the main indication for a hysterectomy in the United States and occur in 25% of women >35 years. Because uterine leiomyomata can form when ovariectomized guinea pigs are exposed to estradiol and retinoic acids, we tested whether human leiomyomata had high levels of retinoic acids and related nuclear receptors. Compared with normal human myometrium, leiomyomata had 3- to 5-fold higher levels of peroxisome proliferator-activated receptor gamma (PPARgamma), retinoid X receptor alpha proteins, and all-trans retinoic acid, but only during the follicular phase of the menstrual cycle. 9-cis Retinoic acid was undetectable in either leiomyomata or myometrium. PPARgamma mRNA levels were lower in leiomyomata than myometrium, but only during the luteal phase of the cycle. A PPARgamma agonist, troglitazone, was given to guinea pigs along with estradiol and all-trans retinoic acid and produced the largest leiomyomata seen to date in this model. By contrast, no tumors formed when troglitazone was given alone or with estradiol or when troglitazone was given with estradiol and 9-cis retinoic acid. New therapies for human leiomyomata may emerge by combining antagonists for PPARgamma and retinoid X receptor alpha with selective estrogen receptor modulators.

Insulin binding to human ovaries.

Human ovarian tissue samples were obtained at the time of laparotomy, and plasma membrane fractions were prepared and used in receptor assays. Incubations of the membrane fraction were performed with [125I]insulin (porcine), and Scatchard analysis of binding showed biphasic curves. The high affinity sites had an average concentration of 57.4 +/- 7.9 (+/- SEM) fmol/mg protein and a dissociation constant of 3.5 +/- 0.9 nM (n = 9). Neither affinity nor number of binding sites changed significantly during the menstrual cycle. We conclude that there is high affinity binding of [125I]insulin to human ovarian plasma membranes.

Insulin receptors in circulating erythrocytes and monocytes from women on oral contraceptives or pregnant women near term.

Altered carbohydrate metabolism occurs in women during pregnancy and in those using oral contraceptives (OC). Insulin binding to circulating erythrocytes and monocytes was studied in 77 nonobese, healthy women volunteers; they were divided into 4 groups: 1) late pregnant (n = 19),2) OC users taking 50 microgram estrogen daily (OC-50; n = 19),3) OC users taking 35 microgram estrogen daily (OC-35; n = 18), and 4) a control group (n = 21). All nonpregnant volunteers were in the luteal phase (days 18-21) of the menstrual cycle. Oral glucose tolerance tests were normal in all groups. Fasting plasma insulin was higher (P < 0.001) in the pregnant group, and plasma insulin responses to the oral glucose tolerance test were higher (P < 0.05) in the pregnant, OC-35, and OC-50 groups compared to that in the control group. The percentage of specific binding of [125I]insulin to 1.2 x 10(7) monocytes/ml (and 4.4 x 10(9) erythrocytes/ml) was similar in all groups (mean +/- SE): pregnant, 6.85 +/- 0.48% (6.85 +/- 0.59%); OC-35, (6.85 +/- 0.40%); OC-50, 6.95 +/- 0.55% (6.73 +/- 0.59%); and control 6.66 +/- 0.64% (7.17 +/- 0.44%). No correlation was found between insulin binding to erythrocytes and monocytes. Average affinity profiles and binding sites per cell (70/erythrocyte and 50,000/monocyte, respesctively) were similar in all groups. Since insulin binding to monocytes in decreased during the secretory phase of the menstrual cycle, one could extrapolate from our data that pregnant women will have lower insulin binding compared to nonpregnant women in the proliferative phase of the cycle; such a report has appeared recently (Beck-Nielsen et al., J Clin Endocrinol Metab 49: 810, 1979). Differences in plasma levels of estrogen and progesterone between the secretory and proliferative phases of the cycle are much smaller than between the nonpregnant state and late pregnancy. Therefore, it remains to be seen whether these steroid hormones would cause, by the same mechanism, a decrease in insulin binding (and insulin resistance) during late pregnancy and in the secretory phase of the cycle.

PIP: This study of altered carbohydrate metabolism in pregnant women and oral contraceptive (OC) users measured insulin binding to circulating erythrocytes and monocytes in 77 nonobese healthy women volunteers. The 77 women were divided into 4 groups: 1) third trimester pregnant (n=19); 2) OC users using 50 mcg estrogen formulations (n=19; OC50); 3) OC users with 35 mcg formulations (n=18; OC35); and 4) controls (n=21). Nonpregnant participants in the study were between menstrual cycle Days 18 and 21 (luteal phase). Oral glucose tolerance tests were performed on all groups, and results were normal for all 4 groups. When fasting plasma insulin was tested, it was higher (P .001) in the pregnant group, and plasma insulin responses to oral glucose tolerance test were higher (p .05) in the pregnant, OC35, and OC 50 groups compared with controls. Specific binding of tritiated insulin to monocytes showed similar percentage in all 4 groups. There was no correlation between insulin binding to erythrocytes and monocytes. The average affinity profiles and binding sites per cell (70/erythrocyte and 50,000/monocyte) were similar in all groups as well.

Distribution of guaiacol peroxidase in human endometrium and endocervical epithelium during the menstrual cycle.

Guaiacol peroxidase (G-Px) was measured in extracts from five sections along the length of human uterus on different days of the menstrual cycle or after menopause. The lower uterine-endocervical region had a significantly higher G-Px content (expressed as enzyme units per g wet tissue) than the other sections, although in postmenopausal patients the G-Px activity was uniformly low in all sections of the uterine cavity. We observed no significant changes in G-Px levels during the menstrual cycle, except, possibly, a decrease around ovulation, which precluded a positive correlation between plasma estrogen levels and uterine G-Px content; such estrogen dependence of G-Px has been previously shown in the rat. In vitro, G-Px was inhibited by estriol and 17 beta-estradiol, marginally inhibited by estrone, and most notably inhibited by the catecholestrogens tested (2-hydroxy-17 beta-estradiol, 2-hydroxy-estriol, and 2-hydroxy-estrone), which were equipotent inhibitors; LH and FSH, progesterone, or cortisol had no effect on G-Px activity. We hypothesize that catecholestrogens are natural substrates and regulations of G-Px activity in the human uterus.

Tumor necrosis factor-alpha upregulates the prostaglandin E2 EP1 receptor subtype and the cyclooxygenase-2 isoform in cultured amnion WISH cells.

Recent studies have demonstrated a strong correlation between infection and preterm labor. Preterm delivery is also associated with high levels of cytokines and prostaglandins in amniotic fluid. The purpose of this study was to investigate the effect of tumor necrosis factor-alpha (TNF-alpha) on the levels of cyclooxygenase, prostaglandin E2 production (PGE2), and expression of the PGE2 receptor subtype EP1 in amnion WISH cell culture. Amnion WISH cell cultures were incubated in increasing concentrations of TNF-alpha (0-50 ng/ml). Changes in cyclooxygenase and EP1 receptor proteins were evaluated by Western blot analysis. Changes in EP1 mRNA were evaluated by Northern blot, and culture fluid concentrations of PGE2 were estimated by enzyme immunoassay (EIA). EP1 protein (p<0.01), EP1 mRNA (p<0.05), cyclooxygenase-2 (COX-2) protein (p<0.001), and PGE2 concentrations (p<0.01) all increased with increasing concentrations of TNF-alpha. Changes in COX-1 protein were not observed following TNF-alpha-incubation. The results suggest that TNF-alpha may play a role in infection-induced preterm labor by its pleiotropic ability to simultaneously stimulate COX-2 activity, PGE2 concentrations, and PGE2 EP1 receptor levels in human amnion.

Elevated umbilical cord plasma erythropoietin levels in prolonged pregnancies.

OBJECTIVE: To determine if umbilical cord plasma erythropoietin levels are elevated in pregnancies that continue beyond their expected date for delivery. METHODS: Erythropoietin was measured using an enzyme-linked immunosorbent assay in 124 appropriately grown newborns delivered from 37-43 weeks' gestation. Each woman had an uncomplicated labor and delivery course without evidence of fetal stress or meconium. The comparison was made between pregnancies ending at 37-40 weeks' gestation and those at 41-43 weeks' gestation. RESULTS: There was no difference between the two groups in cord blood gases or Apgar scores at 1 and 5 minutes. Cord plasma erythropoietin levels were significantly higher in pregnancies delivered after 41 completed weeks' gestation (41 or more weeks: 48.0+/-7.1 mIU/mL, n=45 versus 37-40 weeks: 26.1+/-4.2 mIU/mL, n=79, P < .001). When compared with pregnancies delivered between 37 and 40 weeks, erythropoietin levels were significantly elevated in pregnancies delivered at either 41, 42, or 43 weeks' gestation. CONCLUSION: In pregnancies reaching 41 weeks and beyond, cord plasma erythropoietin levels are significantly increased, indicating altered fetal oxygenation in some of these pregnancies. These results support the current practice of close fetal surveillance of prolonged pregnancies.

Modulation of the prostaglandin E receptor: a possible mechanism for infection-induced preterm labor.

OBJECTIVE: To evaluate the modulatory effects of interleukin (IL)-1beta and prostaglandin (PG)E2 on the PGE2 receptor subtype EP1 in amnion cell cultures. METHODS: Amnion cell cultures were incubated in increasing concentrations of (IL)-1beta or PGE2. Cultures were also incubated in high concentrations of IL-1beta and PGE2 in combination. Changes in EP1 receptor levels were evaluated by western and northern blot analysis. Culture fluid PGE2 levels were measured by enzyme-linked immunosorbent assay. RESULTS: EP1 receptor protein levels decreased with increasing levels of PGE2 (r = -0.82, P < .05). EP1 receptor protein (r = 0.95, P < .05), EP1 mRNA (r = 0.95, P < .01), and culture fluid PGE2 levels (P < .01) were all increased after IL-1beta administration. EP1 receptor levels also increased approximately fourfold in response to IL-1beta incubation even in the presence of high agonist (PGE2) concentrations (P < .01). CONCLUSION: The results of this study show that IL-1beta might be involved in infection-induced preterm labor by interfering with the normal regulation of EP1 receptor levels and with the promotion of increased PGE2 production in amnion tissue.

Cervicovaginal peroxidases: markers of the fertile period.

The specific activity of guaiacol peroxidase was measured daily in human cervical mucus, vaginal fluids, and saliva during 45 cycles in 31 women. Also determined were basal body temperatures and serum hormones (luteinizing hormone [LH], estradiol, progesterone). The guaiacol peroxidase was extracted with 0.5 M CaCl2 and thus may be a different peroxidase from that obtained by noncalcium extraction procedures. The guaiacol peroxidase specific activity did not vary in the saliva during the cycle but fell sharply in the cervical mucus and vaginal fluid four to five days before the ovulation time, estimated by the LH peak, and rose again one to two days after ovulation. Anovulatory cycles did not show the midcycle drop in guaiacol peroxidase. Growth curve analysis gave excellent fitting of the guaiacol peroxidase data to a polynominal model. These data suggest that cervicovaginal guaiacol peroxidase may be clinically useful in detecting the fertile period for population control and for infertility treatment.

The effects of two triphasic oral contraceptives on carbohydrate metabolism in women during 1 year of use.

Sixty-one women were randomly assigned to use one of two different triphasic oral contraceptives (OCs), for one year's time (Ortho Novum 777, Ortho Pharmaceutical Corp., Raritan, NJ, and Triphasil, Wyeth Laboratories, Philadelphia, PA), containing the progestins norethindrone and levonorgestrel, respectively. The carbohydrate metabolism was evaluated using the oral glucose tolerance test before OC use and at the end of the 12th month. Both plasma glucose and insulin levels were measured. The fasting glucose value in the norethindrone-containing OC group (777) was significantly lower at the 1-year testing. All other values were unchanged. These data demonstrate that the triphasic oral contraceptive preparations currently in use have minimal effects on carbohydrate metabolism.

PIP: Carbohydrate metabolism was investigated over 1-year period in new users of 2 different triphasic oral contraceptives (OCs)--Ortho Novum 777, which contains the progestin norethindrone, and Triphasil, in which levonorgestrel is the progestin. The 2 groups of women were similar in terms of age, parity, and weight. Carbohydrate metabolism was assessed through use of the oral glucose tolerance test before the onset of OC use and again after 12 months of use. In terms of plasma glucose results, only 1 value changed significantly during the study period; fasting glucose was lower than baseline in women taking the norethindrone triphasic OC. There was no significant change among users of either triphasic during the study period in plasma insulin levels. It is now believed that the elevations in birth plasma glucose and insulin levels recorded in earlier studies of OC users reflected the effects of the high dose of synthetic steroids used in these formulations, especially the progestins. The OCs that have been used since the 1980s indicate that low amounts of estrogen also improve carbohydrate metabolism, presumably by inhibiting the degradation of insulin. There are some indications that norgestrel tends to have a greater adverse effect on carbohydrate metabolism than norethindrone, perhaps accounting for the lowered fasting glucose in users of the norethindrone triphasic OC in this study. With norethindrone, the estrogen effect on carbohydrate metabolism predominates, but no significant fasting glucose change seems to occur when levonorgestrel counters the estrogen's improving effects on carbohydrates. Overall, these findings provide reassurance that the triphasic OCs currently in use have minimal effects on carbohydrate metabolism in addition to providing good cycle control and high rates of protection against pregnancy.

Cervicovaginal peroxidases: sex hormone control and potential clinical uses.

Thirty-one normal women were studied daily in 41 cycles. Venous blood samples were taken for measurements of luteinizing hormone (LH), estradiol (E2), and progesterone (P), and vaginal examinations were done to obtain cervical mucus and vaginal fluid. The specific activity of guaiacol peroxidase (GP), extracted from cervicovaginal secretions with 0.5 M CaCl2, was determined in the vaginal samples. In the follicular phase, from day -7 to day 0 (the LH +1 day, when ovulation presumably occurred), there was a strong negative correlation between GP and the rising E2 (r = -0.94). On days 1 to 10 after ovulation, there was a strong positive correlation between GP and P (r = 0.84). In nine ovulatory cycles in which P levels did not exceed 8 ng/ml on any day, indicating possible luteal phase inadequacy, there were significantly lower GP levels than in another 32 ovulatory cycles with higher P (P = 0.04). These results suggest that (1) at midcycle, E2 seems to "down-regulate" the GP specific activity; and (2) in the luteal phase, serum P levels parallel those of GP activity, even in the presence of high luteal E2. GP activity profiles during the menstrual cycle can be used to define the fertile period, may prove useful in diagnosing pregnancy, and may be a simple, convenient test for an inadequate corpus luteum.

Insulin and insulin-like growth factor I in brain tumors: binding and in vitro effects.

We have measured insulin and insulin-like growth factor I (IGF-I) binding in human gliomas, meningiomas, and normal brain and studied the effect of insulin on the morphology, proliferation, and differentiation of central nervous system tumor and normal fetal cells in culture. Specific 125I-insulin and 125I-IGF-I binding was demonstrated by competition-inhibition binding assays. Insulin binding was measured in plasma membrane preparations from 9 freshly isolated human meningiomas, 4 glioblastomas multiforme (GBMs), a low-grade glioma, a normal adult brain, and a fetal brain. IGF-I binding was measured in similar preparations from 5 meningiomas, 4 GBMs, a low-grade glioma, and a normal adult brain. Incubations were carried out at 4 degrees C for 18 to 20 hours. Meningiomas showed higher specific insulin binding per 0.25 mg of protein than GBMs (19% versus 3%, P less than 0.005), and this difference was not related to small differences observed in insulin degradation. By contrast, IGF-I binding was significantly higher in gliomas than in meningiomas (27% versus 12%, P less than 0.05). Also, IGF-I binding was significantly higher than insulin binding in GBMs (27% versus 3%, P less than 0.03); binding of both IGF and insulin was high in meningiomas. In normal adult brain IGF-I and insulin binding was 7 to 10%. The ability of insulin to support and enhance the growth of central nervous system tumor cells in culture was investigated. Cell cultures were derived from a freshly isolated glioblastoma, a low-grade glioma, and 3 meningiomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma glucose and insulin levels in women using a levonorgestrel-containing triphasic oral contraceptive for three months.

Plasma glucose and insulin levels were measured for three hours after an oral glucose challenge in twenty-nine women before and after using a triphasic oral contraceptive containing ethinyl estradiol and levonorgestrel for three months. There were significant elevations in the glucose levels during the three-month tolerance test, while the insulin levels were unchanged. These data suggest that this OC can alter carbohydrate metabolism and that long-term studies are needed to assess the extent of this metabolic change.

PIP: This study investigates the effects of low steroid triphasic contraceptive pills on blood glucose and insulin levels. 29 women, given glucose tolerance tests to establish normality, were then given the triphasic oral contraceptive Triphasil (ethinyl estradiol and levonorgestrel) for 3 months. In all of the women blood glucose values were significantly elevated after 3 months; insulin levels were unaffected. Since estrogens have little effect on carbohydrate metabolism, the effect must be due to the progestin norgestrel. Drug manufacturers dislike lowering the progestin content of pills because the progestins control cyclic bleeding, but their longterm effects need to be evaluated.

The effect of sex steroids on insulin binding by target tissues in the rat.

The effect of estradiol, progesterone and norgestrel on serum insulin and glucose levels and on insulin binding to adipocytes, hepatocytes and diaphragm muscle cell membranes has been evaluated in castrated male rats. Estradiol administration (5 micrograms/day X 6) significantly increased basal plasma insulin levels and the amount of insulin bound to fat and liver cells as well as muscle cell membranes. Progesterone treatment (5 mg/day X 6) caused a slight increase of basal insulin levels and a decrease of insulin binding to fat cells. Norgestrel treatment (5 mg/day X 6) decreased both insulin levels and the amount of insulin bound to adipocytes; a much lower dose of norgestrel, 6 micrograms/day X 7, also caused a decline in adipocyte insulin binding due to an apparent increase in the dissociation constant of the high affinity binding sites. These studies demonstrate that ovarian sex steroids have a significant effect on insulin binding to target cells. This animal model would assist in determining the mechanisms involved in changes of carbohydrate metabolism which occur during the menstrual cycle, pregnancy, the menopausal state and with the use of oral contraceptives.

Six-month carbohydrate metabolism studies in women using oral contraceptives containing gestodene and ethinyl estradiol.

Twenty-five women had their carbohydrate metabolism prospectively evaluated during the six months that they used a gestodene and ethinyl estradiol monophasic oral contraceptive. Serum glucose and insulin levels were measured during a 75-gram three-hour oral glucose tolerance test. At the six-month test, the three-hour glucose and the fasting and three-hour insulin values were significantly elevated. The literature on carbohydrate metabolism during gestodene oral contraceptive use is also reviewed.

PIP: The effects of combination-type oral contraceptives (OCs) (containing 75 mcg of the progestin gestodene and 30 mcg of ethinyl estradiol [EE] on carbohydrate metabolism during 6 months of use was evaluated in 25 women with a mean age of 26.1 +or- 1.1 years, parity of .7 +or- .1, and mean control weight of 143.5 +or- 6.1 pounds. An oral glucose tolerance test was performed after a 10-hour fast and a venous blood sample was taken. After drinking 75 g of glucose, repeat blood samples were drawn. After 6 cycles of OC use each subject was given another oral glucose tolerance test. The mean weight was 144.2 +or- 6.2 pounds. No complications and pregnancies occurred. The serum glucose 3-hour value was significantly elevated at the 6-month test. Also, significant increase of the fasting and 3-hour values of insulin were found. The results suggest that gestodene is capable of altering carbohydrate metabolism via its androgen receptor activity. Triphasic preparations (1650 mcg of gestodene and 680 mcg of EE) have a similar effect on carbohydrate metabolism as do monophasic pills (1575 mcg of gestodene and 630 mcg of EE) because of similar total steroid dose. OCs containing low-dose gestodene may alter carbohydrate metabolism to some extent but the longterm effects require further investigation as such new OCs have not been proved to be superior to existing formulations.

Carbohydrate metabolism studies after one year of using an oral contraceptive containing gestodene and ethinyl estradiol.

UNLABELLED: The objective of the study is to evaluate the effects of a gestodene-containing oral contraceptive on carbohydrate metabolism. The design of the study is prospective. The setting is at University of South Florida Outpatient Unit. The patients consisted of twenty-three normal women desiring contraception. Serum glucose and insulin levels were measured during a three-hour glucose tolerance test at control time and after one year of drug use. RESULTS: All of the one-year glucose values were significantly elevated as well as the fasting and three-hour insulin values. These changes were mostly confined to women over 26 years of age and not in the younger 18 to 23 year olds. An oral contraceptive containing 75 micrograms of gestodene and 30 micrograms of ethinylestradiol can significantly alter carbohydrate metabolism in older women.

PIP: In Tampa over a 1-year period, health workers followed 23 normal 18-34 year old women, who came to the University of South Florida Outpatient Unit for an oral contraceptive (OC) prescription, to examine the carbohydrate metabolic effects of an OC containing 75 mcg gestodene and 30 mcg ethinyl estradiol. No one conceived. All the glucose values increased significantly over the 12-month study period (p = .002). The significant increase was restricted to only women in the 26-34 year old group at fasting and 0.5, 1, and 2 hours (p .05), however. The fasting and 3 hour insulin values were significantly elevated (p .001 and .002, respectively). The elevated insulin values were largely confined to the 26-34 year old group (at 0.5, 1, and 3 hours), but they were also elevated at fasting and 3 hours in the 18-23 year old group. Even though the values of carbohydrate metabolic parameters were significantly elevated, the values were in the normal physiologic range. Since gestodene has little estrogen binding capacity and estrogen improves carbohydrate metabolism, this combined OC tends to have adverse effects on carbohydrate metabolism, particularly in older women. Longer and larger duration studies are needed to examine whether these effects increase or reverse with time.

Guaiacol peroxidase levels in human cervical mucus: a possible predictor of ovulation.

PIP: Guaiacol peroxidase (G-Px) is an enzyme which in the human uterine epithelium has been found to be inhibited in vitro by estrogens and especially catecholestrogens. This study determines if the concentration of G-Px would vary inversely to plasma estrogens. It is hoped that this enzyme would decrease sufficiently early before ovulation to be useful as a simple predictor of ovulation in women. G-Px was serially measured in cervical mucus during the menstrual cycle of 5 healthy volunteers. Radioimmunoassay measured the following hormones in the plasma samples: 17 beta-estradiol, progesterone, luteinizing and follicle stimulating hormones. In the midcycle, G-Px levels decreased 20- to 100-fold relative to other times of the cycle, the decrease coinciding with the peak of plasma estrogens and probably causally related to them. G-Px levels were not affected by the 2nd peak of plasma estrogens, possibly because of the counter effect of progesterone. Further research should be done to determine possible hormonal control of G-Px activity. G-Px may be central to the structure and function of cervical mucus. They may have bactericidal and spermicidal properties and may play a role in sperm capacitation. The findings in this study may be beneficial in estimating optimal time for intercourse and artificial insemination in infertile patients and improving the efficacy of the periodic abstinence method of contraception by easily identifying the fertile period. In addition, the G-Px assay in cervical mucus is adaptable to a simple sensitive home test because the products of guaiacol oxidation are visible to the naked eye and drastic changes in color production can be easily perceived.^ieng

Carcinogen activation by human uterine enzymes.

Three topics are briefly reviewed relating to carcinogenesis of estrogen responsive tissues: (a) enzymology of benzo(a)pyrene activation by human tissues, (b) microsomal activation of estrogens to estrogen arene oxides and (c) estrogen and progesterone receptor studies in endometrial carcinoma. The following working hypothesis is stated on the etiology of gynecologic tumors: "Environmental chemicals, such as cigarette smoke, polycyclic and polyhalogenated hydrocarbons, etc., induce special forms of cytochrome P-450 monooxygenase and related enzyme systems which can activate endogenous or prescribed estrogens and non-steroid antiestrogens to act as initiators and/or promoters of neoplasia in estrogen-dependent organs." The role of estrogen receptors is perceived as a homing device or cellular "Trojan Horse" for these activated estrogens.

Fetal erythropoietin levels in growth-restricted and appropriately grown neonates with and without abnormal fetal heart rate tracings: a comparison with cord blood gases and Apgar scores.

OBJECTIVE: To determine if umbilical cord plasma erythropoietin (EPO) levels in combination with cord blood gases and Apgar scores can distinguish between subacute and chronic uteroplacental insufficiency. METHODS: A total of 184 neonates delivered between 1993 and 1997 at Tampa General Hospital were studied. Cord plasma EPO levels, cord blood gases, and Apgar scores were determined prospectively and compared in four subgroups that were defined based on the presence or absence of fetal growth restriction (FGR; chronic fetal hypoxia), abnormal fetal heart rate tracings during labor (FHR; subacute/acute fetal hypoxia), or both. RESULTS: Both growth-restricted and appropriately grown newborns with abnormal intrapartum FHR tracing had elevated umbilical cord plasma EPO (183.5 and 135.2 mIU/ml, respectively; normal = 20.7 mIU/ml) and base deficit, whereas pH, Po2, and 1-minute and 5-minute Apgar scores were significantly lower, compared with appropriately grown newborns with a normal intrapartum course. Among newborns with normal heart rate tracings and FGR, the mean plasma EPO levels were elevated (89.5 mIU/ml), whereas the other parameters were not different from normal. CONCLUSION: Our findings suggest that, although cord blood gases and Apgar scores may reflect subacute and acute events, they are not good predictors of chronic uteroplacental insufficiency. The supplemental use of umbilical cord plasma EPO levels may improve our ability to identify chronic uteroplacental insufficiency.