Developmental regulation of baboon fetal ovarian maturation by estrogen

Ovarian function in adult human and nonhuman primates is dependent on events that take place during fetal development, including the envelopment of oocytes by granulosa (i.e., folliculogenesis). However, our understanding of fetal ovarian folliculogenesis is incomplete. During baboon pregnancy, placental production and secretion of estradiol into the fetus increases with advancing gestation, and the fetal ovary expresses estrogen receptors alpha and beta in mesenchymal-epithelial cells (i.e., pregranulosa) as early as midgestation. Therefore, the current study determined whether estrogen regulates fetal ovarian follicular development. Pregnant baboons were untreated or treated with the aromatase inhibitor CGS 20267, or with CGS 20267 plus estradiol benzoate administered s.c. to the mother on Days 100-164 (term = Day 184). On Day 165, baboon fetuses were delivered by cesarean section and the number of total follicles and interfollicular nests consisting of oocytes and mesenchymal-epithelial cells in areas (0.33 mm(2)) of the outer and inner cortices of each fetal ovary were quantified using image analysis. Maternal and umbilical serum estradiol levels were decreased by >95% with CGS 20267. Treatment with CGS 20267 and estrogen restored maternal estradiol to normal and fetal estradiol to 30% of normal. Although fetal ovarian weight was unaltered, the mean number of follicles +/- SEM/0.33 mm(2) in the inner (59.0 +/- 1.7) and outer (95.3 +/- 2.4) cortical regions of fetal ovaries in untreated animals was 35%-50% lower (P < 0.01) in estrogen-depleted baboons (25.9 +/- 1.4, inner cortex; 62.5 +/- 2.7, outer cortex) and was restored to normal by treatment with CGS 20267 and estrogen. In contrast, the number of interfollicular nests was 2-fold greater (P < 0.01) in fetal ovaries of estrogen-suppressed animals, a change that was prevented by treatment with estrogen. In summary, fetal ovarian follicular development was significantly altered in baboons in which estrogen was depleted during the second half of gestation and restored to normal by estradiol. We propose that estrogen plays an integral role in regulating, and perhaps programming, primate fetal ovarian development.     

Normal concentrations of essential and toxic elements in pregnant baboons and fetuses (Papio species)

Heavy metals are essential for the normal progression of maternal and fetal tissue growth and metabolism in pregnancy. Considerable data have been collected for concentrations of various elements in pregnant women, but no comprehensive evaluation of element concentrations in any non-human primate model has been performed. Baboons were studied at the second half of pregnancy. Forty essential and toxic element concentrations were analyzed by absorption spectrophotometry in paired maternal and fetal blood samples; hair and nail samples in pregnant baboons; in placenta, amniotic fluid; and fetal femur, lymph nodes, and liver. Concentrations demonstrated an excellent correlation with concentrations reported in late human pregnancy. Twenty-four elements were below detectable limits in various specimens. We conclude that the pregnant baboon offers unique opportunities to study both normal maternal, fetal, and placental physiology as well as the environmental toxicology of these elements. This information and the ability to use the pregnant baboon as a model is important because essential and toxic elements are key components of the diet as well as major products of manufacturing processes within our industrialized society.     

Source and regulation of 17 alpha-hydroxyprogesterone during baboon pregnancy

The present study determined the source and regulation of 17 alpha-hydroxyprogesterone (17-OHP4) during mid-late baboon pregnancy. Serum 17-OHP4 (ng/ml) in 5 untreated baboons increased from low values at mid-late gestation to a mean (+/- SEM) of 0.49 +/- 0.02 during the final 20 days of gestation. Fetectomy of 5 baboons resulted in serum 17-OHP4 concentrations which declined to and remained at baseline. Serum 17-OHP4 concentrations were 5- to 10-fold greater (P less than 0.001) in the uterine, utero-ovarian, and umbilical veins than peripherally. Apparently the fetal adrenal provides precursors for placental 17-OHP4 formation because the fetal adrenal gland develops delta 5-3 beta-hydroxysteroid dehydrogenase only late in gestation, and because the fetal adrenal and not the placenta has the capacity for 17-hydroxylation. Thus, at mid-late gestation the placenta appears to supply a major, and at term the corpus luteum a minor portion of the total 17-OHP4. Administration of the estrogen antagonist ethamoxytriphetol (MER-25, 15 mg/kg BW) to 4 baboons did not affect 17-OHP4 during mid-late gestation, when the placenta was the only source of 17-OHP4. However, MER-25 resulted in serum 17-OHP4 concentrations (ng/ml) at term which were greater (1.08 +/- 0.10, P less than 0.001) than in untreated baboons (0.49 +/- 0.02). Prior removal of the corpus luteum of pregnancy in 4 animals subsequently given MER-25 prevented this rise in 17-OHP4. This suggests that the marked elevation in 17-OHP4 observed near term after MER-25 administration was of luteal origin and that antiestrogen enhanced 17-OHP4 secretion by the corpus luteum.     

The timed-pregnant baboon animal model can be used for determining the role of soluble vascular endothelial growth factor receptors 1 and 2 during development

BACKGROUND: During pregnancy, mechanisms that allow for regulation of continuous fetal and placental vasculogenesis with prevention of maternal neo-vascularization remain elusive. The vascular endothelial growth factor (VEGF) biological system has a key role during vasculogenesis. The aims of this study were to validate a bioassay for soluble vascular endothelial growth factor receptors 1 and 2 (sVEGFR-1 and sVEGFR-2) in baboon plasma and to determine the maternal and fetal plasma concentration of these receptors at the end of the baboon pregnancy. METHODS: Maternal peripheral blood samples were obtained from eight baboons (Papio anubis) prior to elective cesarean section and from the umbilical cord after the fetuses were delivered. Spike and recovery experiments at various concentrations in pooled baboon maternal plasma were used to validate a human quantitative sandwich immunoassay for sVEGFR-1 and -2. Concentrations of sVEGFR-1 and -2 were then determined in maternal and fetal plasma samples. RESULTS: No significant correlations were observed between sVEGFR-1 or -2 concentrations in maternal and fetal circulations. The concentration of sVEGFR-1 was at least 30 times greater and that of sVEGFR-2 approximately two times greater, in maternal than in cord plasma (both P < 0.01). CONCLUSION: These findings suggest that baboons can be used to study the regulation of vasculogenesis during pregnancy.     

Fetal blood sampling in baboons (Papio spp.): Important procedural aspects and literature review

Background  The baboons ( Papio cynocephalus ) have similarities with human placentation and fetal development. Fetal blood sampling allows investigators to assess fetal condition at a specific point in gestation as well as transplacental transfer of medications. Unfortunately, assessing fetal status during gestation has been difficult and fetal instrumentation associated with high rate of pregnancy loss. Our objectives are to describe the technique of ultrasound guided cordocentesis (UGC) in baboons, report post-procedural outcomes, and review existing publications.
Methods  This is a procedural paper describing the technique of UGC in baboons. After confirming pregnancy and gestational age via ultrasound, animals participating in approved research protocols that required fetal assessment underwent UGC.
Results  We successfully performed UGC in four animals (five samples) using this technique. Animals were sampled in the second and third trimesters with fetal blood sampling achieved by sampling a free cord loop, placental cord insertion site or the intrahepatic umbilical vein. All procedures were without complication and these animals delivered at term.
Conclusions  Ultrasound guided fetal umbilical cord venipuncture is a useful and safe technique to sample the fetal circulation with minimal risk to the fetus or mother. We believe this technique could be used for repeated fetal venous blood sampling in the baboons.     

Glucose-stimulated insulin response in pregnant sheep following acute suppression of plasma non-esterified fatty acid concentrations

Background  

Elevated non-esterified fatty acids (NEFA) concentrations in non-pregnant animals have been reported to decrease pancreatic responsiveness. As ovine gestation advances, maternal insulin concentrations fall and NEFA concentrations increase. Experiments were designed to examine if the pregnancy-associated rise in NEFA concentration is associated with a reduced pancreatic sensitivity to glucose in vivo. We investigated the possible relationship of NEFA concentrations in regulating maternal insulin concentrations during ovine pregnancy at three physiological states, non-pregnant, non-lactating (NPNL), 105 and 135 days gestational age (dGA, term 147+/- 3 days).     

Up-regulation of alpha-inhibin expression in the fetal ovary of estrogen-suppressed baboons is associated with impaired fetal ovarian folliculogenesis

We recently demonstrated that the number of primordial follicles was significantly reduced in the ovaries of near-term baboon fetuses deprived of estrogen in utero and restored to normal in animals administered estradiol. Although the baboon fetal ovary expressed estrogen receptors alpha and beta, the mechanism(s) of estrogen action remains to be determined. It is well established that inhibin and activins function as autocrine/paracrine factors that impact adult ovarian function. However, our understanding of the expression of these factors in the primate fetal ovary is incomplete. Therefore, we determined the expression of alpha-inhibin, activin beta(A), activin beta(B), and activin receptors in fetal ovaries obtained at mid and late gestation from untreated baboons and at late gestation from animals in which fetal estrogen levels were reduced by >95% by maternal administration of the aromatase inhibitor CGS 20267 or restored to 30% of normal by treatment with CGS 20267 and estradiol benzoate. Immunocytochemical expression of alpha-inhibin was minimal to nondetectable in fetal ovaries from untreated baboons. In contrast, in baboons depleted of estrogen, alpha-inhibin was abundantly expressed in pregranulosa cells of interfollicular nests and granulosa cells of primordial follicles. Thus, the number (mean +/- SEM) per 0.08 mm2 of fetal ovarian cells expressing alpha-inhibin, determined by image analysis, was similar at mid and late gestation and increased approximately 8-fold (P < 0.01) near term in baboons treated with CGS 20267 and was restored (P < 0.01) to normal in baboons treated with CGS 20267 plus estradiol. Activin beta(A) was detected in oocytes and pregranulosa cells at midgestation and in oocytes and granulosa cells of primordial follicles at late gestation. Activin beta(B) was also expressed in pregranulosa cells and granulosa cells at mid and late gestation, respectively, but was not detected in oocytes. Neither the pattern nor the apparent level of expression of activin beta(A) or beta(B) were altered in fetal ovaries of baboons treated with CGS 20267 or CGS 20267 and estrogen. Activin receptors IA, IB, IIA, and IIB were detected by Western blot analysis in fetal ovaries at mid and late gestation, and expression was not altered by treatment with CGS 20267 or CGS 20267 and estrogen. Activin receptors IB and IIA were localized to oocytes and pregranulosa cells at midgestation and to granulosa cells and oocytes of primordial follicles at late gestation. Thus, the decrease in the number of follicles in the primate fetal ovary of baboons deprived of estrogen in utero was associated with increased expression of alpha-inhibin. Therefore, we propose that estrogen regulates fetal ovarian follicular development by controlling alpha-inhibin expression and, thus, the intraovarian inhibin:activin ratio.     

Suppression of trophoblast uterine spiral artery remodeling by estrogen during baboon pregnancy: impact on uterine and fetal blood flow dynamics

The present study was conducted to determine the impact of suppressing trophoblast remodeling of the uterine spiral arteries by prematurely elevating estrogen levels in the first trimester of baboon pregnancy on uterine and umbilical blood flow dynamics. Uteroplacental blood flow was assessed by Doppler ultrasonography after acute administration of saline (basal state) and serotonin on days 60, 100, and 160 of gestation (term: 184 days) to baboons in which uterine spiral artery remodeling had been suppressed by the administration of estradiol on days 25-59 of gestation. Maternal blood pressure in the basal state was increased (P < 0.01), and uterine artery diastolic notching and the umbilical artery pulsatility index and systolic-to-diastolic ratio, reflecting downstream flow impedance, were increased (P < 0.01) after serotonin administration on day 160, but not earlier, in baboons treated with estradiol in early gestation. These changes in uteroplacental flow dynamics in serotonin-infused, estradiol-treated animals were accompanied by a decrease (P < 0.05) in uterine and umbilical artery volume flow and fetal bradycardia. The results of this study show that suppression of uterine artery remodeling by advancing the rise in estrogen from the second trimester to the first trimester disrupted uteroplacental blood flow dynamics and fetal homeostasis after vasochallenge late in primate pregnancy.     

Chronic umbilical cord compression results in accelerated maturation of lung and brown adipose tissue in the sheep fetus during late gestation

Umbilical cord compression (UCC) sufficient to reduce umbilical blood flow by 30% for 3 days, results in increased fetal plasma cortisol and catecholamines that are likely to promote maturation of the fetal lung and brown adipose tissue (BAT). We determined the effect of UCC on the abundance of uncoupling protein (UCP)1 (BAT only) and -2, glucocorticoid receptor (GR), and 11beta-hydroxysteroid dehydrogenase (11beta-HSD)1 and -2 mRNA, and mitochondrial protein voltage-dependent anion channel (VDAC) and cytochrome c in these tissues. At 118 +/- 2 days of gestation (dGA; term approximately 145 days), 14 fetuses were chronically instrumented. Eight fetuses were then subjected to 3 days of UCC from 125 dGA, and the remaining fetuses were sham operated. All fetuses were then exposed to two 1-h episodes of hypoxemia at 130 +/- 1 and 134 +/- 1 dGA before tissue sampling at 137 +/- 2 dGA. In both tissues, UCC upregulated UCP2 and GR mRNA, plus VDAC and cytochrome c mitochondrial proteins. In lung, UCC increased 11beta-HSD1 mRNA but decreased 11beta-HSD2 mRNA abundance, a pattern reversed for BAT. UCC increased UCP1 mRNA and its translated protein in BAT. UCP2, GR, 11beta-HSD1 and -2 mRNA, plus VDAC and cytochrome c protein abundance were all significantly correlated with fetal plasma cortisol and catecholamine levels, but not thyroid hormone concentrations, in the lung and BAT of UCC fetuses. In conclusion, chronic UCC results in precocious maturation of the fetal lung and BAT mitochondria, an adaptation largely mediated by the surge in fetal plasma cortisol and catecholamines that accompanies UCC.     

Effect of estrogen on the metabolism of cortisol and cortisone in the baboon fetus at midgestation

To determine whether the metabolism of cortisol (F) and cortisone (E) in the baboon fetus is regulated by estrogen, fetal interconversion of F/E was measured at midgestation after an experimental increase in placental estradiol (E2) production. Six baboons (Papio anubis) received increasing numbers of androstenedione implants (50 mg) inserted s.c. at 8-day intervals between Days 70 and 100 of gestation (term = Day 184) to elevate the production of estrogen; controls (N = 8) received no treatment. On Day 100 of gestation, each animal was anesthetized with ketamine:halothane/nitrous oxide, the fetus was exteriorized and [3H] F/[14C] E was infused via a fetal femoral vein for 70 min. Blood samples were then obtained from the contralateral fetal femoral vein, the umbilical vein/artery, and a maternal saphenous vein. After purification of F and E, the metabolic clearance rate (MCR), peripheral interconversion, and placental extraction of F and E were calculated. Maternal serum E2 concentrations (ng/ml; mean +/- SE) between Days 80 and 100 of gestation were greater (p less than 0.01) in androstenedione-treated baboons (2.2 +/- 0.2) than in untreated controls (1.2 +/- 0.1). Although the MCR of F was similar in control (5.2 +/- 0.3 1/day) and treated (7.7 +/- 1.0 1/day) animals, the MCR of E (13.5 +/- 2.0 1/day) was increased (25.8 +/- 2.5 1/day; p less than 0.05) by androstenedione treatment. Placental extraction of F (59 +/- 9%) was lower (p less than 0.01) than that of E (82 +/- 5%) in untreated baboons and was not affected by androstenedione treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

The endocrinology of pregnancy and fetal loss in wild baboons

An impressive body of research has focused on the mechanisms by which the steroid estrogens (E), progestins (P), and glucocorticoids (GC) ensure successful pregnancy. With the advance of non-invasive techniques to measure steroids in urine and feces, steroid hormones are routinely monitored to detect pregnancy in wild mammalian species, but hormone data on fetal loss have been sparse. Here, we examine fecal steroid hormones from five groups of wild yellow baboons (Papio cynocephalus) in the Amboseli basin of Kenya to compare the hormones of successful pregnancies to those ending in fetal loss or stillbirth. Using a combination of longitudinal and cross-sectional data, we analyzed three steroid hormones (E, P, GC) and related metabolites from 5 years of fecal samples across 188 pregnancies. Our results document the course of steroid hormone concentrations across successful baboon pregnancy in the wild and demonstrate that fecal estrogens predicted impending fetal loss starting 2 months before the externally observed loss. By also considering an additional 450 pregnancies for which we did not have hormonal data, we determined that the probability for fetal loss for Amboseli baboons was 13.9%, and that fetal mortality occurred throughout gestation (91 losses occurred in 656 pregnancies; rates were the same for pregnancies with and without hormonal data). These results demonstrate that our longstanding method for early detection of pregnancies based on observation of external indicators closely matches hormonal identification of pregnancy in wild baboons.     

Placental uptake and transport of ACP, a neutral nonmetabolizable amino acid, in an ovine model of fetal growth restriction

Reductions in fetal plasma concentrations of certain amino acids and reduced amino acid transport in vesicle studies suggest impaired placental amino acid transport in human fetal growth restriction (FGR). In the present study, we tested the hypothesis of an impairment in amino acid transport in the ovine model of hyperthermia-induced FGR by determining transplacental and placental retention and total placental clearance of a branched-chain amino acid (BCAA) analog, the nonmetabolizable neutral amino acid aminocyclopentane-1-carboxylic acid (ACP), in singleton control (C) and FGR pregnancies at 135 days gestation age (dGA; term 147 dGA). At study, based on the severity of the placental dysfunction, FGR fetuses were allocated to severe (sFGR, n = 6) and moderate FGR (mFGR, n = 4) groups. Fetal (C, 3,801.91 +/- 156.83; mFGR, 2,911.33 +/- 181.35; sFGR, 1,795.99 +/- 238.85 g; P < 0.05) and placental weights (C, 414.38 +/- 38.35; mFGR, 306.23 +/- 32.41; sFGR, 165.64 +/- 28.25 g; P < 0.05) were reduced. Transplacental and total placental clearances of ACP per 100 g placenta were significantly reduced in the sFGR but not in the mFGR group, whereas placental retention clearances were unaltered. These data indicate that both entry of ACP into the placenta and movement from the placenta into fetal circulation are impaired in severe ovine FGR and support the hypothesis of impaired placental BCAA transport in severe human FGR.     

Sonographic biometrical normograms and estimation of fetal weight in the baboon (Papio anubis)

Background  In order to consider the non-human primate as an adequate model for studying prenatal diagnosis and therapy, comparative data on fetal growth should be available.
Methods  Sixty ultrasound scans were performed in 22 baboons between 14 and 167 days of gestation. Measurements included greatest length, head circumference, biparietal diameter (BPD), transcerebellar diameter, abdominal circumference (AC), femur length (FL), and amniotic fluid index. For all parameters growth curves were established and compared with human curves. In 18 animals, birth weight and placental weight were determined. Different equations described in the literature for estimating the human fetal weight were tested in the baboon.
Results  The fetal and placental growth pattern in the baboon was comparable with humans. The best predictor of fetal weight was the formula presented by Combs: 0.23966 × AC² × FL + 1.623 × BPD³.
Conclusions  A high similarity between baboon and human growth charts is shown. The best equation for estimating the baboon fetal weight is proposed.     

Maternal testosterone and fetal sex

To investigate the influence of fetal sex on maternal testosterone levels throughout pregnancy, blood was sampled from 37 healthy pregnant women from week 14 until term and at 6 weeks postpartum. Testosterone concentrations were measured with a highly specific RIA after chromatographic purification. Mean (+/- SD) testosterone at the end of gestation was significantly higher compared to non-pregnant values (3.10 +/- 2.38 mM/l, n = 32 vs 1.14 +/- 1.06 nM/l, n = 35). It appeared that in women carrying a male fetus testosterone levels gradually increased during pregnancy up to 3.99 +/- 2.72 nM/l. In women carrying a female fetus the levels decreased after the first trimester from 2.44 nM/l to 1.80 nM/l. A statistically significant difference (P less than 0.01) existed in maternal testosterone concentrations between both groups during the second half of pregnancy.     

Regulation of placental villous angiopoietin-1 and -2 expression by estrogen during baboon pregnancy

We recently showed an increase in vascular endothelial growth factor (VEGF), decrease in angiopoietin-1 (Ang-1) and unaltered Ang-2 expression by the villous placenta with advancing baboon pregnancy. Moreover, placental VEGF expression was increased by estrogen in early pregnancy. In the present study, we determined whether placental Ang-1 and Ang-2 are regulated by estrogen. Ang-1 and Ang-2 mRNA and protein were determined by RT-PCR and immunocytochemistry in the placenta of baboons on Day 60 of gestation (term is 184 days) after administration of estrogen precursor androstenedione on Days 25-59 or on Day 54 after acute estradiol administration. Chronic androstenedione treatment increased serum estradiol levels three-fold (P < 0.001) and decreased (P < 0.05) villous cytotrophoblast Ang-1 mRNA to a level (0.36 +/- 0.08 relative to 18S rRNA) that was one-third of that in untreated animals (0.98 +/- 0.26). Within 2 hr of estradiol administration, cytotrophoblast Ang-1 mRNA was decreased to a level (0.24 +/- 0.05) one-fifth (P < 0.05) of that in untreated animals (1.14 +/- 0.23). However, Ang-2 mRNA levels were unaltered. Ang-1, Ang-2 and estrogen receptors alpha and beta protein were localized within villous cytotrophoblasts providing a mechanism for estrogen action at this site. In summary, estrogen increased VEGF, decreased Ang-1, and had no effect on Ang-2 expression within placental cytotrophoblasts during early baboon pregnancy. We propose that the estrogen-dependent differential regulation of these angioregulatory factors underpins the unique pattern of neovascularization established within the villous placenta during primate pregnancy.     

Fetal growth in the baboon during the second half of pregnancy

The normal growth profile of critical fetal organs through the last third of gestation has not been documented in detail in human fetuses or the fetus of any nonhuman primate species. Recent epidemiological studies in human pregnancy suggest that fetal growth plays a major role in the programming of life-long health by modifying cardiovascular, pancreatic, brain, and liver growth. The present study aimed to produce a detailed database of individual organ growth in the fetal baboon in late gestation. Fetal organ weights were obtained from 43 baboon fetuses between 121 and 177 days of gestation. Various organs (brain, heart, kidney, femur, intestines, and spinal cord) showed no sign of slowed growth in late gestation while growth of others (lung, liver, stomach, and bladder) accelerated in late gestation. The fetal adrenal and thymus showed a decrease in growth rate over the final 20 and 10 days of gestation respectively. These observations provide a database that will permit analysis of factors responsible for regulation of normal and altered fetal organ development in this important experimental species.     

Functional capacity of fetal zone cells of the baboon fetal adrenal gland: a major source of alpha-inhibin.

We have shown that ACTH receptor mRNA expression and steroidogenesis were increased in the transitional zone and decreased in the fetal zone of the baboon fetal adrenal in the second half of gestation. Thus, we proposed that there is a divergence in ACTH receptor-mediated zone-specific steroidogenesis within the fetal adrenal during mid to late gestation. We have also demonstrated that fetal serum alpha-inhibin levels decline with advancing development. It is possible, therefore, that the alpha subunit of inhibin provides a good marker of fetal zone cellular function and that the changes in circulating fetal alpha-inhibin with advancing pregnancy reflect ontogenetic changes in fetal adrenal cortical zone-specific cell function. However, it remains to be determined whether the fetal adrenal is a major source of circulating alpha-inhibin in the fetus and whether alpha-inhibin is expressed in the fetal, definitive, and/or transitional zones. Therefore, the current study compared fetal serum alpha-inhibin levels with immunocytochemical localization of alpha-inhibin in baboon fetal adrenals obtained on Days 60 (early), 100 (mid), and 165 or 182 (late) of gestation (term averages Day 184) from animals untreated or treated with betamethasone, which we previously demonstrated suppressed fetal pituitary ACTH and adrenal weight. Fetal serum alpha-inhibin levels (mean +/- SE) were greater (p < 0.05) at mid (5863 +/- 730 microliter eq/ml) than at late (3246 +/- 379) gestation and were reduced (p < 0. 05) by betamethasone. The inhibin alpha subunit was expressed in abundant quantities in the fetal adrenal cortex, but not in medulla, throughout gestation. At mid and late gestation, alpha-inhibin was expressed throughout the fetal adrenal cortex but most intensely in the innermost area of fetal zone cells. By late gestation, the fetal adrenal exhibited a gradient of alpha-inhibin expression. Thus, the outermost definitive zone cells were devoid of alpha-inhibin, the transitional zone exhibited a relatively low alpha-inhibin content, and fetal zone cells continued to exhibit extensive expression of alpha-inhibin. Betamethasone diminished the intensity of alpha-inhibin expression throughout the fetal adrenal cortex. These results indicate that the fetal adrenal fetal zone is a significant source of circulating alpha-inhibin in the baboon fetus and that alpha-inhibin provides a good marker to study the developmental regulation of fetal zone-specific adrenocortical function.     

Plasma levels of the immunomodulatory cytokine interleukin-10 during normal human pregnancy: a longitudinal study

Pregnancy is proposed to be a Th2 phenomenon, where Th2 cytokines inhibit Th1 responses to improve foetal survival. The importance of interleukin-10 (IL-10), an immunomodulatory cytokine produced by Th2 cells, in the maintenance of normal pregnancy is becoming increasingly apparent. In a longitudinal case-control study, the physiological effect of pregnancy on plasma IL-10 was investigated. The plasma concentration of IL-10 was determined using an ELISA technique in 99 pregnant women sampled at 12, 20 and 35 weeks of gestation, 38 non-pregnant control subjects sampled in parallel and in a subgroup of women sampled at 3 days post-partum (n, pregnant 21, non-pregnant 21). Plasma IL-10 was significantly higher in pregnant women at 12, 20 and 35 weeks of gestation (p<0.05, p<0.01 and p<0.0001, respectively), and in mothers post-delivery (p<0.01) when compared to non-pregnant control subjects. Furthermore, there was no significant effect of gestational time on IL-10 concentration. Results from the current study suggest that elevated IL-10 is a physiological consequence of normal healthy pregnancy. These findings help clarify previous conflicting results and establish a range for plasma levels of IL-10 in normal healthy pregnancy.