Immunology in wild nonmodel rodents: an ecological context for studies of health and disease.

Transcriptomic methods are set to revolutionize the study of the immune system in naturally occurring nonmodel organisms. With this in mind, the present article focuses on ways in which the use of 'nonmodel' rodents (not the familiar laboratory species) can advance studies into the classical, but ever relevant, epidemiologic triad of immune defence, infectious disease and environment. For example, naturally occurring rodents are an interesting system in which to study the environmental stimuli that drive the development and homeostasis of the immune system and, by extension, to identify where these stimuli are altered in anthropogenic environments leading to the formation of immunopathological phenotypes. Measurement of immune expression may help define individual heterogeneity in infectious disease susceptibility and transmission and facilitate our understanding of infection dynamics and risk in the natural environment; furthermore, it may provide a means of surveillance that can filter individuals carrying previously unknown acute infections of potential ecological or zoonotic importance. Finally, the study of immunology in wild animals may reveal interactions within the immune system and between immunity and other organismal traits that are not observable under restricted laboratory conditions. Potentiating much of this is the possibility of combining gene expression profiles with analytical tools derived from ecology and systems biology to reverse engineer interaction networks between immune responses, other organismal traits and the environment (including symbiont exposures), revealing regulatory architecture. Such holistic studies promise to link ecology, epidemiology and immunology in natural systems in a unified approach that can illuminate important problems relevant to human health and animal welfare and production.

Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open-label trial.

AIMS: To compare efficacy and safety of two, once-daily basal insulin formulations [insulin lispro protamine suspension (ILPS) vs. insulin glargine (glargine)] added to oral antihyperglycaemic medications (OAMs) and exenatide BID in suboptimally controlled type 2 diabetes (T2D) patients. METHODS: This 24-week, open-label, multicentre trial randomized patients to bedtime ILPS (n = 171) or glargine (n = 168). Non-inferiority of ILPS versus glargine was assessed by comparing the upper limit of 95% confidence intervals (CIs) for change in haemoglobin A1c (HbA1c) from baseline to week 24 (adjusted for baseline HbA1c) with non-inferiority margin 0.4%. RESULTS: Non-inferiority of ILPS versus glargine was demonstrated: least-squares mean between-treatment difference (ILPS minus glargine) (95% CI) was 0.22% (0.06, 0.38). Mean HbA1c reduction was less for ILPS- versus glargine-treated patients (-1.16 ± 0.84 vs. -1.40 ± 0.97%, p = 0.008). Endpoint HbA1c < 7.0% was achieved by 53.7% (ILPS) and 61.7% (glargine) (p = NS). Overall hypoglycaemia rates (p = NS) and severe hypoglycaemia incidence (p = NS) were similar. Nocturnal hypoglycaemia rate was higher in patients treated with ILPS versus glargine (p = 0.004). Weight gain was similar between groups (ILPS: 0.27 ± 3.38 kg; glargine: 0.66 ± 3.93 kg, p = NS). Endpoint total insulin doses were lower in patients treated with ILPS versus glargine (0.30 ± 0.17 vs. 0.37 ± 0.17 IU/kg/day, p < 0.001). CONCLUSIONS: ILPS was non-inferior to glargine for HbA1c change over 24 weeks, but was associated with less HbA1c reduction and more nocturnal hypoglycaemia. Treat-to-target basal insulin therapy improves glycaemic control and is associated with minimal weight gain when added to OAMs and exenatide BID for suboptimally controlled T2D.

Host-parasite biology in the real world: the field voles of Kielder.

Research on the interactions between the field voles (Microtus agrestis) of Kielder Forest and their natural parasites dates back to the 1930s. These early studies were primarily concerned with understanding how parasites shape the characteristic cyclic population dynamics of their hosts. However, since the early 2000s, research on the Kielder field voles has expanded considerably and the system has now been utilized for the study of host-parasite biology across many levels, including genetics, evolutionary ecology, immunology and epidemiology. The Kielder field voles therefore represent one of the most intensely and broadly studied natural host-parasite systems, bridging theoretical and empirical approaches to better understand the biology of infectious disease in the real world. This article synthesizes the body of work published on this system and summarizes some important insights and general messages provided by the integrated and multidisciplinary study of host-parasite interactions in the natural environment.

Macroparasites at peripheral sites of infection are major and dynamic modifiers of systemic antimicrobial pattern recognition responses.

Immune defences and the maintenance of immunological homeostasis in the face of pathogenic and commensal microbial exposures are channelled by innate antimicrobial pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). Whilst PRR-mediated response programmes are the result of long-term host-pathogen or host-commensal co-evolutionary dynamics involving microbes, an additional possibility is that macroparasitic co-infections may be a significant modifier of such interactions. We demonstrate experimentally that macroparasites (the model gastrointestinal nematode, Heligmosomoides) at peripheral sites of infection cause substantial alteration of the expression and function of TLRs at a systemic level (in cultured splenocytes), predominantly up-regulating TLR2, TLR4 and TLR9-mediated cytokine responses at times of high standing worm burdens. We consistently observed such effects in BALB/c and C57BL/6 mice under single-pulse and trickle exposures to Heligmosomoides larvae and in SWR and CBA mice under single-pulse exposures. A complementary long-term survey of TLR2-mediated tumour necrosis factor-alpha responses in wild wood mice (Apodemus sylvaticus) was consistent with substantial effects of macroparasites under some environmental conditions. A general pattern, though, was for the associations of macroparasites with TLR function to be temporally dynamic and context-dependent: varying with different conditions of infection exposure in the field and laboratory and with host genetic strain in the laboratory. These results are compelling evidence that macroparasites are a major and dynamic modifier of systemic innate antimicrobial responsiveness in naturally occurring mammals and thus likely to be an important influence on the interaction between microbial exposures and the immune system.

Urinary chemokines CXCL9 and CXCL10 are noninvasive markers of renal allograft rejection and BK viral infection.

Renal transplant recipients require periodic surveillance for immune-based complications such as rejection and infection. Noninvasive monitoring methods are preferred, particularly for children, for whom invasive testing is problematic. We performed a cross-sectional analysis of adult and pediatric transplant recipients to determine whether a urine-based chemokine assay could noninvasively identify patients with rejection among other common clinical diagnoses. Urine was collected from 110 adults and 46 children with defined clinical conditions: healthy volunteers, stable renal transplant recipients, and recipients with clinical or subclinical acute rejection (AR) or BK infection (BKI), calcineurin inhibitor (CNI) toxicity or interstitial fibrosis (IFTA). Urine was analyzed using a solid-phase bead-array assay for the interferon gamma-induced chemokines CXCL9 and CXCL10. We found that urine CXCL9 and CXCL10 were markedly elevated in adults and children experiencing either AR or BKI (p = 0.0002), but not in stable allograft recipients or recipients with CNI toxicity or IFTA. The sensitivity and specificity of these chemokine assays exceeded that of serum creatinine. Neither chemokine distinguished between AR and BKI. These data show that urine chemokine monitoring identifies patients with renal allograft inflammation. This assay may be useful for noninvasively distinguishing those allograft recipients requiring more intensive surveillance from those with benign clinical courses.

The Southern Ocean Exchange: porous boundaries between humpback whale breeding populations in southern polar waters.

Humpback whales (Megaptera novaeangliae) are a cosmopolitan species and perform long annual migrations between low-latitude breeding areas and high-latitude feeding areas. Their breeding populations appear to be spatially and genetically segregated due to long-term, maternally inherited fidelity to natal breeding areas. In the Southern Hemisphere, some humpback whale breeding populations mix in Southern Ocean waters in summer, but very little movement between Pacific and Atlantic waters has been identified to date, suggesting these waters constituted an oceanic boundary between genetically distinct populations. Here, we present new evidence of summer co-occurrence in the West Antarctic Peninsula feeding area of two recovering humpback whale breeding populations from the Atlantic (Brazil) and Pacific (Central and South America). As humpback whale populations recover, observations like this point to the need to revise our perceptions of boundaries between stocks, particularly on high latitude feeding grounds. We suggest that this "Southern Ocean Exchange" may become more frequent as populations recover from commercial whaling and climate change modifies environmental dynamics and humpback whale prey availability.

Big and slow: phylogenetic estimates of molecular evolution in baleen whales (suborder mysticeti).

Baleen whales are the largest animals that have ever lived. To develop an improved estimation of substitution rate for nuclear and mitochondrial DNA for this taxon, we implemented a relaxed-clock phylogenetic approach using three fossil calibration dates: the divergence between odontocetes and mysticetes approximately 34 million years ago (Ma), between the balaenids and balaenopterids approximately 28 Ma, and the time to most recent common ancestor within the Balaenopteridae approximately 12 Ma. We examined seven mitochondrial genomes, a large number of mitochondrial control region sequences (219 haplotypes for 465 bp) and nine nuclear introns representing five species of whales, within which multiple species-specific alleles were sequenced to account for within-species diversity (1-15 for each locus). The total data set represents >1.65 Mbp of mitogenome and nuclear genomic sequence. The estimated substitution rate for the humpback whale control region (3.9%/million years, My) was higher than previous estimates for baleen whales but slow relative to other mammal species with similar generation times (e.g., human-chimp mean rate > 20%/My). The mitogenomic third codon position rate was also slow relative to other mammals (mean estimate 1%/My compared with a mammalian average of 9.8%/My for the cytochrome b gene). The mean nuclear genomic substitution rate (0.05%/My) was substantially slower than average synonymous estimates for other mammals (0.21-0.37%/My across a range of studies). The nuclear and mitogenome rate estimates for baleen whales were thus roughly consistent with an 8- to 10-fold slowing due to a combination of large body size and long generation times. Surprisingly, despite the large data set of nuclear intron sequences, there was only weak and conflicting support for alternate hypotheses about the phylogeny of balaenopterid whales, suggesting that interspecies introgressions or a rapid radiation has obscured species relationships in the nuclear genome.

A comparison of baleen whale density estimates derived from overlapping satellite imagery and a shipborne survey.

As whales recover from commercial exploitation, they are increasing in abundance in habitats that they have been absent from for decades. However, studying the recovery and habitat use patterns of whales, particularly in remote and inaccessible regions, frequently poses logistical and economic challenges. Here we trial a new approach for measuring whale density in a remote area, using Very-High-Resolution WorldView-3 satellite imagery. This approach has capacity to provide sightings data to complement and assist traditional sightings surveys. We compare at-sea whale density estimates to estimates derived from satellite imagery collected at a similar time, and use suction-cup archival logger data to make an adjustment for surface availability. We demonstrate that satellite imagery can provide useful data on whale occurrence and density. Densities, when unadjusted for surface availability are shown to be considerably lower than those estimated by the ship survey. However, adjusted for surface availability and weather conditions (0.13 whales per km2, CV = 0.38), they fall within an order of magnitude of those derived by traditional line-transect estimates (0.33 whales per km2, CV = 0.09). Satellite surveys represent an exciting development for high-resolution image-based cetacean observation at sea, particularly in inaccessible regions, presenting opportunities for ongoing and future research.

Safety and efficacy of glargine compared with NPH insulin for the treatment of Type 2 diabetes: a meta-analysis of randomized controlled trials.

AIMS: We systematically analysed evidence from randomized controlled trials (RCTs) examining the safety and efficacy of neutral protamine Hagedorn (NPH) insulin and glargine in the management of adults with Type 2 diabetes. METHODS: Studies were identified by searching medline (1966-March 2007), embase (1974-2007), American Diabetes Association abstract database and the Cochrane Central Register of Controlled Trials using Medical Subject Headings (MeSH) diabetes mellitus, Type 2, insulin, insulin isophane, hypoglycaemic agents and the keywords glargine and NPH. Data on study design, participants, fasting plasma glucose (FPG), glycated haemoglobin (HbA(1c)), body weight and hypoglycaemia were independently abstracted by two investigators using a standardized protocol. RESULTS: Data from a total of 4385 participants in 12 RCTs were pooled using a random-effects model. The mean net change (95% confidence interval) for FPG, HbA(1c) and body weight for patients treated with NPH insulin as compared with glargine was 0.21 mmol/l (-0.02 to 0.45), 0.08% (-0.04 to 0.21) and -0.33 kg (-0.61 to -0.06), respectively, with negative values favouring NPH and positive values favouring glargine. More participants experienced symptomatic and nocturnal hypoglycaemia on NPH than glargine, but there was no significant difference in confirmed or severe episodes. CONCLUSIONS: We identified no difference in glucose-lowering between insulin glargine and NPH insulin, but less patient-reported hypoglycaemia with glargine and slightly less weight gain with NPH in adults with Type 2 diabetes.

Measuring immune system variation to help understand host-pathogen community dynamics.

Carefully chosen immunological measurements, informed by recent advances in our understanding of the diversity and control of immune mechanisms, can add great interpretative value to ecological studies of infection. This is especially so for co-infection studies, where interactions between species are often mediated via the host's immune response. Here we consider how immunological measurements can strengthen inference in different types of co-infection analysis. In particular, we identify how measuring immune response variables in field studies can help reveal inter-species interactions otherwise obscured by confounding processes operating on count or prevalence data. Furthermore, we suggest that, due to the difficulty of quantifying microbial pathogen communities in field studies, innate responses against broad pathogen types (mediated by pattern response receptors) may be useful quantitative markers of exposure to bacteria and viruses. An ultimate goal of ecological co-infection studies may also be to understand how dynamics within host-parasite assemblages emerge from trade-offs involving different arms of the immune system. We reflect on the phenotypic measures that might best represent levels of responsiveness and bias in immune function. These include mediators associated with different T-helper cell subsets and innate responses controlled by pattern response receptors, such as the Toll-like receptors (TLRs).

The cost of infection: Argulus foliaceus and its impact on the swimming performance of the three-spined stickleback (Gasterosteus aculeatus).

For fish, there can be multiple consequences of parasitic infections, including the physical impacts on swimming and the pathological costs of infection. This study used the three-spined stickleback (Gasterosteus aculeatus) and the ectoparasitic fish louse, Argulus foliaceus, to assess both physical (including form drag and mass) and pathological effects of infection. Both sustained (prolonged swimming within an open channel flume) and burst (C-start) swimming performance were measured on individual fish before (trials 1-2) and after infection (trials 3-5). Experimental infection occurred shortly before the third trial, when the physical impacts of infection could be separated from any subsequent pathology as transmission of adult parasites causes instantaneous drag effects prior to observable pathology. Despite the relatively large size of the parasite and corresponding increase in hydrodynamic drag for the host, there were no observable physical effects of infection on either sustained or burst host swimming. By contrast, parasite-induced pathology is the most probable explanation for reduced swimming performance across both tests. All sticklebacks displayed a preference for flow refugia, swimming in low-velocity regions of the flume, and this preference increased with both flow rate and infection time. This study suggests that even with large, physically demanding parasites their induced pathology is of greater concern than direct physical impact.

Global biogeographic patterns in bipolar moss species.

A bipolar disjunction is an extreme, yet common, biogeographic pattern in non-vascular plants, yet its underlying mechanisms (vicariance or long-distance dispersal), origin and timing remain poorly understood. Here, combining a large-scale population dataset and multiple dating analyses, we examine the biogeography of four bipolar Polytrichales mosses, common to the Holarctic (temperate and polar Northern Hemisphere regions) and the Antarctic region (Antarctic, sub-Antarctic, southern South America) and other Southern Hemisphere (SH) regions. Our data reveal contrasting patterns, for three species were of Holarctic origin, with subsequent dispersal to the SH, while one, currently a particularly common species in the Holarctic (Polytrichum juniperinum), diversified in the Antarctic region and from here colonized both the Holarctic and other SH regions. Our findings suggest long-distance dispersal as the driver of bipolar disjunctions. We find such inter-hemispheric dispersals are rare, occurring on multi-million-year timescales. High-altitude tropical populations did not act as trans-equatorial 'stepping-stones', but rather were derived from later dispersal events. All arrivals to the Antarctic region occurred well before the Last Glacial Maximum and previous glaciations, suggesting that, despite the harsh climate during these past glacial maxima, plants have had a much longer presence in this southern region than previously thought.

Effects on performance and meat quality of Holstein bulls fed high concentrate diets without implants following immunological castration.

The objective of this study was to evaluate the effect of the GnRH vaccine on the performance and meat quality of Holstein bulls fed high concentrate diets. A total of 493 approximately 7month old bulls (initial BW 298±1.2kg) were allocated into 3 treatment groups, intact bulls (n=164), animals surgically castrated at 15 to 17d of the study (n=164), and animals vaccinated on 0 and 28d of the study with the GnRH vaccine (n=165). Animals were slaughtered between 131 and 133d and carcass quality was evaluated. Hot carcass weight, dressing percentage, fat classification and meat quality parameters did not differ significantly between surgically castrated and vaccinated animals but differed (P<0.05) from intact bulls. Carcass classification, pH at 26h, and fat color were not affected by treatment.

Heterogeneous interspecific interactions in a host-parasite system.

Macroparasites of vertebrates usually occur in multi-species communities, producing infections whose outcome in individual hosts or host populations may depend on the dynamics of interactions amongst the different component species. Within a single co-infection, competition can occur between conspecific and heterospecific parasite individuals, either directly or via the host's physiological and immune responses. We studied a natural single-host, multi-parasite model infection system (polystomes in the anuran Xenopus laevis victorianus) in which the parasite species show total interspecific competitive exclusion as adults in host individuals. Multi-species infection experiments indicated that competitive outcomes were dependent on infection species composition and strongly influenced by the intraspecific genetic identity of the interacting organisms. Our results also demonstrate the special importance of temporal heterogeneity (the sequence of infection by different species) in competition and co-existence between parasite species and predict that developmental plasticity in inferior competitors, and the induction of species-specific host resistance, will partition the within-host-individual habitat over time. We emphasise that such local (within-host) context-dependent processes are likely to be a fundamental determinant of population dynamics in multi-species parasite assemblages.

Meiotic recombination between duplicated genetic elements in Saccharomyces cerevisiae.

We have studied the meiotic recombination behavior of strains carrying two types of duplications of an 18.6-kilobase HIS4 Bam HI fragment. The first type is a direct duplication of the HIS4 Bam HI fragment in which the repeated sequences are separated by Escherichia coli plasmid sequences. The second type, a tandem duplication, has no sequences intervening between the repeated yeast DNA. The HIS4 genes in each region were marked genetically so that recombination events between the duplicated segments could be identified. Meiotic progeny of the strains carrying the duplication were analyzed genetically and biochemically to determine the types of recombination events that had occurred. Analysis of the direct vs. tandem duplication suggests that the E. coli plasmid sequences are recombinogenic in yeast when homozygous. In both types of duplications recombination between the duplicated HIS4 regions occurs at high frequency and involves predominantly interchromosomal reciprocal exchanges (equal and unequal crossovers). The striking observation is that intrachromosomal reciprocal recombination is very rare in comparison with interchromosomal reciprocal recombination. However, intrachromosomal gene conversion occurs at about the same frequency as interchromosomal gene conversion. Reciprocal recombination events between regions on the same chromatid are the most infrequent exchanges. These data suggest that intrachromosomal reciprocal exchanges are suppressed.

Adult onset idiopathic familial brain calcifications.

We treated a family with idiopathic calcifications of symmetric areas of the brain, including the basal ganglia, dentate, and cerebral white matter. Dementia, progressive dysarthria, incontinence, propulsive-ataxic gait, fixed facies, and cogwheel rigidity without dysmorphic features develop in affected persons. Calcium, phosphorus, and parathyroid hormone levels were normal in the two siblings tested. The literature is reviewed and five other families with a similar syndrome are identified. These six families seem to be clinically distinct from the larger group of idiopathic cerebral calcifications usually referred to as Fahr's disease.

Prostatic complications of testosterone replacement therapy.

The prostatic complications of testosterone replacement therapy have received little clinical attention. We describe three hypogonadal men who had prostatic disease (adenocarcinoma in two) detected in relation to such therapy. Literature review suggests that surveillance for early prostate cancer is appropriate during replacement therapy in men over the age of 50 years. We discuss the selective use of digital rectal examination, transrectal sonography, directed prostate biopsy, and prostate-specific antigen determinations before therapy and in subsequent follow-up in this age group of men during androgen replacement.

Euthyroid hyperthyroxinemia and inappropriate secretion of thyrotropin. Recognition and diagnosis.

Various disease states associated with euthyroid hyperthyroxinemia and inappropriate thyrotropin secretion are becoming increasingly recognized. These diagnoses were established in six (11%) of 57 patients referred for evaluation of elevated free thyroxine index over an 11-month period. Failure to separate these entities from primary thyrotoxicosis may result in unnecessary thyroid ablative therapy and subsequent clinical confusion. Several illustrative patient summaries are presented to outline an approach to this clinical challenge.

Effect of anti-gonadotropin-releasing factor vaccine and band castration on indicators of welfare in beef cattle.

Angus crossbred bulls (n = 60; 257 ± 5.4 d of age; initial BW 358.8 ± 3.78 kg) were used to study the effect of a vaccine against gonadotropin-releasing factor (GnRF) and band castration on behavioral and physiological indicators of pain. Cattle were randomly assigned to 1 of 3 treatments: bulls, band-castrated calves without pain mitigation (castrated), and immune-vaccinated animals administered an anti-GnRF vaccine (vaccinated). All animals were fitted with a radio frequency ear tag so that individual animal feed intake and feeding behavior were recorded daily over the entire trial using an electronic feed bunk monitoring system. Two doses of anti-GnRF vaccine were administrated on d -35 and 0 and band castration was performed on d 0. Animal BW was recorded weekly starting on d -36 until d 56. Visual analog scores (VAS) were measured on d -36 -35, -1, and 0, and salivary cortisol concentration was measured at -30, 0, 30, 60, 120, and 270 min on d -35 and 0 after castration. Saliva and blood were obtained on d 1, 2, 5, and 7 and weekly until d 56 for determination of cortisol and complete blood cell count. Video data were collected for pain, sexual, and aggressive behavior daily the first week and once a week until d 56. Data were analyzed with a mixed-effect model with castration, time, and their interactions as main effects. Vaccinated calves had reduced ADG and intake (P < 0.05 and P < 0.001, respectively) during the first week after vaccination. Band-castrated calves had reduced ADG and intake (P < 0.001) until the end of the study. No differences in salivary cortisol and VAS were observed among groups at d -35 after the first vaccination and before band castration. However, on d 0, castrated cattle had greater cortisol concentrations and VAS (P < 0.05 and P < 0.01, respectively) than bulls and vaccinated animals. Complete blood cell count did not differ (P > 0.05) between treatments on d 0, 1, and 2. At d 56, vaccinated calves had greater (P < 0.05) final BW than band-castrated calves and both had less final BW than bulls. There was no indication that vaccination caused any physiological or behavioral changes indicative of pain. In contrast, band castration resulted in elevated cortisol scores and VAS indicative of a pain response and behavior related to pain (P < 0.001) until d 42 of the study. The present study demonstrates that anti-GnRF vaccine is a viable animal welfare-friendly alternative to traditional band castration in beef cattle under North American feedlot practices.

Estrogen regulates placental androstenedione production during rat pregnancy.

During rat pregnancy the placenta appears to provide androgens, particularly androstenedione (delta 4A) as a source of precursor for estradiol (E2) formation by the ovary. The present study determined if the ovary and, specifically, estrogen have roles in regulating placental delta 4A production during the second half of rat pregnancy. Pregnant rats were ovariectomized (OVX) on day 9 of gestation, treated daily with 4 mg progesterone (P4) to maintain pregnancy, and received a Silastic capsule containing either E2 or oil on day 10 of gestation only. Placental steroidogenesis was then determined in vitro on day 14 by the ability of this tissue to convert [3H]pregnenolone ([3H]P5) substrate to the intermediate [3H]P4 and product [3H]delta 4A. Mean (+/- SE) placental formation of delta 4A from P5 increased (P less than 0.01) from 6.3 +/- 0.5% in control animals to 10.7 +/- 1.6% in OVX P4-treated rats. In contrast, placentae from OVX animals treated with P4 and E2 exhibited a decline in delta 4A formation (2.5 +/- 0.3%) compared to that in both control (P less than 0.01) and OVX P4-treated (P less than 0.001) animals. The amount of P5 converted to P4 and thus not further metabolized to delta 4A decreased (P less than 0.05) from 64.0 +/- 3.1% in control animals to 49.0 +/- 4.7% in OVX rats treated with P4 alone. However, OVX animals treated with P4 and E2 exhibited an increase in placental conversion of P5 to P4 (80.3 +/- 4.7%) compared to values in both control (P less than 0.05) and OVX P4-treated (P less than 0.001) animals. The peripheral serum concentrations of delta 4A and testosterone (T) were 3- and 2-fold greater (P less than 0.01), respectively, in OVX P4-treated animals compared to concentrations in the untreated controls. Rats that had been OVX and treated with both P4 and E2 had peripheral serum delta 4A and T concentrations that were approximately 10-15% (P less than 0.001) of the concentrations in OVX P4-treated animals. In conclusion, ovariectomy or ovariectomy and estrogen supplementation resulted in comparable alterations in the formation of delta 4A within the placenta and the concentrations of this steroid in the peripheral circulation. Thus, ovariectomy caused an elevation in and ovariectomy with E2 treatment caused a decline in both placental delta 4A formation and peripheral serum androgen concentrations. We suggest, therefore, that ovarian estrogen may feed back to inhibit placental delta 4A and T production, thereby regulating its substrate availability during the second half of rat pregnancy.