The effect of a chronic maternal cortisol infusion on the late-gestation fetal sheep

Exposure of the fetus to excess maternal glucocorticoids has been postulated to alter fetal growth and development, and thus provide a possible mechanism for the link between impaired fetal growth and altered postnatal physiology. However, the effects of exposure to excess maternal glucocorticoids on fetal physiology and metabolism in utero have not been described. We therefore studied the effects of chronic maternal cortisol infusion on fetal growth, blood pressure, metabolism and endocrine status in chronically catheterised fetal sheep. We infused hydrocortisone (80 mg/day, n=6) or saline (n=8) for 10 days into the pregnant ewes beginning at 119 days of gestation. Maternal cortisol infusion reduced fetal growth rate by 30% (girth increment 2.9+/-0.3 vs 1.8+/-0.4 mm/day, P=0.03). Maternal cortisol infusion increased fetal heart weight by 15% relative to body weight and increased ventricular wall thickness by 30% in the left and 50% in the right ventricle. The weight of the spleen was reduced by 30% and placental weight reduced by 25%. Fetal blood pressure increased by approximately 10 mmHg (20%) during maternal cortisol infusion. Maternal cortisol infusion did not alter amino-nitrogen concentrations. However, maternal lactate concentrations increased by 80% and fetal lactate concentrations increased by 74% with maternal cortisol infusion, and both maternal and fetal urea concentrations increased by 40%. Circulating maternal IGF-binding protein (IGFBP)-3 levels had increased by 20% by the end of the maternal cortisol infusion. Fetal IGF-I concentrations decreased during cortisol infusion and fetal IGFBP-1 concentrations were negatively correlated with fetal weight (r=-0.76, P=0.02). We conclude that even a modest elevation of maternal cortisol levels affects fetal growth, cardiovascular function, metabolism and endocrine status which may have long-term consequences.     

Responses of the fetal pituitary-adrenal axis to acute and chronic hypoglycemia during late gestation in the sheep

We investigated the response of the fetal pituitary-adrenal axis to acute and chronic hypoglycemia before and after the normal prepartum activation of this axis at around 135 days gestation (term = 147 +/- 3 days). Pregnant ewes were either well nourished (control group; n = 22) or undernourished (UN; 50% reduction in maternal nutrient intake; n = 23) during the last 30 days of pregnancy. Acute hypoglycemia was induced by intrafetal administration of insulin between 125 and 130 days gestation (control, n = 7; UN, n = 12) and between 138 and 141 days gestation (control, n = 6; UN = 9). Fetal plasma glucose concentrations were significantly lower (P < 0.005) in the UN compared with the control group throughout the insulin infusion period at both gestational age ranges. In the control group, there was no fetal ACTH response to insulin infusion before 135 days gestation, but there was a significant (P < 0.001) response after 136 days gestation. In the UN group, there was a significant ACTH response to insulin infusion both before and after 135 days gestation, and there was no difference in the fetal ACTH response between the two gestational age ranges. The plasma cortisol responses to insulin were greater (P < 0.001) after 136 days compared with before 135 days gestation in both the UN and control groups. In the control group there was no significant relationship between basal fetal plasma ACTH and glucose concentrations between 115-135 days gestation or between 136-145 days gestation. In the UN group, fetal glucose ranged from 0.5-2.0 mM, and plasma ACTH and glucose concentrations were inversely related at 115-135 days gestation [log ACTH = -0.31 (glucose) + 2.21; r = -0.37; P < 0.001] and at 136-145 days gestation [log ACTH = -0.40 (glucose) + 2.50; r = -0.54; P < 0.001]. When the UN and control groups were combined, fetal plasma ACTH concentrations were significantly greater (F = 13.5; P < 0.05) when plasma glucose concentrations were less than 1.0 mM at either 115-135 days or 136-147 days gestation. Similarly, fetal plasma cortisol concentrations were also significantly greater (F = 18.7; P < 0.05) when plasma glucose concentrations were less than 1.0 mM at each gestational age range. Therefore, there is an increased sensitivity of the fetal hypothalamo-pituitary axis to acute falls in glucose concentrations below 1.2 mM after 135 days compared with earlier in gestation. The fetal hypothalamo-pituitary axis can respond, however, when plasma glucose concentrations fall below 1.0 mM, before and after 135 days gestation, independently of whether the low glucose concentrations are a consequence of insulin-induced hypoglycemia or maternal nutrient restriction.     

Regulation of the hypothalamo-pituitary-adrenocortical axis in fetal sheep.

Development of the fetal hypothalamo-pituitary-adrenal (HPA) axis is required for normal fetal life and subsequent neonatal health. Activation of the fetal pituitary gland results in the synthesis and release of glucocorticoids from the adrenal cortex. Glucocorticoids promote maturation of several organ systems, are important in responses of the fetus to stress, and are involved in the initiation of parturition in several species. The expression of hypothalamic and pituitary genes associated with HPA function is apparent early in gestation in fetal sheep, although the endocrine changes associated with maturation and parturition do not occur until the last fifth of gestation. In this connection, the fetal HPA axis can be activated by treatment with hypophysiotrophic factors or moderate stress throughout gestation. This review focuses on the development of neuroendocrine mechanisms controlling HPA function during fetal life.     

The effect of hypothalamo-pituitary disconnection on the functional and morphologic development of the pituitary-adrenal axis in the fetal sheep in the last third of gestation.

We have investigated the effect of hypothalamo-pituitary disconnection (HPD) on the maturation of basal ir-ACTH and cortisol concentrations in fetal sheep plasma, and on the development of the anterior pituitary corticotroph population in the last third of gestation. After HPD, fetal plasma ir-ACTH concentrations were significantly elevated, and continued to rise with increasing gestational age. However, despite elevated ir-ACTH concentrations, there was no increase in fetal plasma cortisol concentrations, and parturition was delayed for at least 8 days beyond normal term. Furthermore, HPD resulted in a significant disruption of the maturation of the pars distalis corticotrophs. We also examined the change in fetal plasma concentrations of ir-ACTH and cortisol to exogenous CRF after HPD. There was a significant increase in plasma ir-ACTH in response to CRF administration in the HPD fetuses, which was qualitatively similar to that observed in sham-operated fetuses. In contrast, the plasma cortisol response was less in HPD fetuses when compared to that in sham-operated fetuses. The results of this study demonstrate that ir-ACTH secretion is not maintained by the fetal hypothalamus in the last third of gestation, and that ir-ACTH secretion is tonically inhibited by the hypothalamus during this time. The disconnection of the pituitary from the hypothalamus disrupts the maturation of the pituitary-adrenal axis, thus demonstrating the fundamental importance of the hypothalamo-pituitary axis in the normal maturational cascade which culminates in birth in this species.     

Development of the pituitary-adrenal axis during fetal life: modalities and regulation

In mammals, the fetal adrenal gland plays a key role during late gestation since the maturation of the fetus and the adaptation of the neonate to extra uterine life mainly depend on glucocorticoids. We review herein the present knowledge concerning the modalities and the endocrine control of the development of the pituitary-adrenal axis in the two most studied models: the ovine and the human fetus. Although the anatomy of the adrenal gland is different in these 2 species, the mechanisms involved in the maturation of adrenocortical cells appear rather similar. Moreover, in both species, the prepartum rise of corticosteroid plasma levels which conveys growth and differentiation of adrenocortical cells, is under pituitary control; this likely involves an increase in the "corticotropic activity" which results from changes in the cleavage of POMC and possibly from a synergistic of inhibitory effect of other hormones with ACTH.     

Early embryonic environment, the fetal pituitary-adrenal axis and the timing of parturition

It is well established in the sheep, that the normal timing of parturition is dependent on a prepartum activation of the fetal pituitary-adrenal axis. We have recently demonstrated for the first time that embryo number, embryo sex, and alterations in the environment of the early embryo, including exposure to maternal undernutrition during the periconceptional period, alter the timing and level of activation of the pituitary-adrenal axis in the sheep fetus during late gestation. There is a delay in activation of the fetal HPA axis in twin fetuses and we speculate that the diminished adrenocortical responsiveness in the twin fetus may be an adaptive response, which counters the impact of the potential enhanced intrauterine stress experienced by a twin fetus, thereby reducing the possibility of preterm delivery. We have also reported that a moderate restriction of maternal nutrition to during the periconceptional period (from 60 days before and for one week after conception) resulted in an earlier activation of the pituitary-adrenal axis of twin, but not singleton, fetuses during late gestation. A series of studies using assisted reproductive technologies have also found that perturbation of the early embryonic environment results in a dysregulation of placental and fetal growth and development and in the timing of normal parturition. In summary, after several decades of work focussed on events in late gestation associated with the prepartum activation and stress responsiveness of the fetal HPA axis, our recent studies indicate that the environment of the early embryo may have a significant role to play in determining the timing and level of the prepartum activation of this axis and potentially on the functional capacity of the axis to respond to acute or chronic stress in later life.     

The development of corticotrophs in the fetal sheep pars distalis: the effect of adrenalectomy or cortisol infusion

At 90 days gestation a uniquely fetal-type and an adult-type corticotroph have been observed in the fetal sheep pars distalis (term approximately 147 days). Between 90 and 130 days gestation the fetal type is predominant, and its numbers decline toward term. In this study the effect of the endogenous cortisol surge on the change in the population of corticotrophs in the pars distalis was investigated in sheep fetuses after bilateral adrenalectomy at 120 days gestation or after an infusion of 2 mg cortisol/day between 109 and 115 days gestation. The total proportion of corticotrophs, expressed as a percentage, decreased significantly (P less than 0.01) from 115 days in saline-infused controls (21.09 +/- 1.10%) and 135 days in intact controls (14.59 +/- 1.12%). The percentage of adult-type corticotrophs increased significantly (P less than 0.01) from 5.65 +/- 0.77 at 115 days, to 11.93 +/- 1.41 at 135 days. The percentage of fetal-type corticotrophs decreased significantly (P less than 0.001) from 14.91 +/- 0.35 at 115 days to 2.33 +/- 0.48 at 135 days. A small proportion of ACTH-immunoreactive cells could not be defined as either adult- or fetal-type corticotrophs. These changes in the corticotroph population had not occurred at 135 days in fetuses that had been adrenalectomized at 120 days; the percentage of corticotrophs relative to unstained cells (21.70 +/- 0.46%), the percentage of adult-type corticotrophs (6.42 +/- 0.29%), and the percentage of fetal-type corticotrophs (14.65 +/- 0.49%) were similar to those in 115-day-old fetuses, indicating that the normal change in the corticotroph population between 115 and 135 days gestation was dependent upon the presence of the fetal adrenal. In fetuses exposed to exogenous cortisol between 109 and 115 days gestation, the percentage of corticotrophs relative to unstained cells (16.53 +/- 1.68%), the percentage of adult-type corticotrophs (12.40 +/- 1.34%), and the percentage of fetal-type corticotrophs (3.78 +/- 0.58%) were similar to those at 135 days. This indicates that a short period of increased fetal plasma cortisol can bring about premature maturation of the corticotrophs in the fetal sheep pars distalis. We have also described an ACTH-immunoreactive cell which has characteristics of both an adult- and a fetal-type corticotroph. Its morphological appearance suggests that it may be a transitional stage from the fetal- to the adult-type corticotroph.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effect of medroxyprogesterone acetate on the pituitary-adrenal axis.

Twelve cancer patients and one patient with diabetes mellitus were treated with medroxyprogesterone acetate (MPA) by intramuscular injection in a total weekly dose of 400, 700, or 1200 mg. The treatment reduced the plasma cortisol concentration by 76% in the AM hours (21 leads to 5.0 mug/dl) and by 75% in the PM hours (12.8 leads to 3.2 mug/dl). Cortisol production rate decreased by 67% (19 leads to 6.2 mg/24 hrs). The 24 hour profile of plasma cortisol concentration measured in 3 patients showed zero secretion over this period. Low plasma ACTH values prevailed during treatment, and a blunted response to maximal ACTH stimulation was found. No evidence of adrenal insufficiency was observed in any patient, even though in some patients the plasma cortisol concentration remained at zero for many weeks. MPA has cortisol-like effects and the suppression of adrenal function is probably mediated by a negative feedback action on the hypothalamus or pituitary.     

Effect of chronic active immunization anti-corticotropin-releasing factor on the pituitary-adrenal function in the sheep.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) or to an acute injection of lysine-vasopressin were studied in intact and anti-corticotropin-releasing factor (CRF) actively immunized rams. Immunization was obtained by the injection of synthetic ovine CRF coupled to BSA with carbodiimide. All animals developed antibodies anti-CRF and displayed an alteration of their general condition and a body weight reduction. The mean basal ACTH and cortisol secretion as well as the number and mean amplitude of diurnal pulses of these hormones was significantly reduced in the group of anti-CRF immunized rams. However, the reduction in all three parameters was much more pronounced for cortisol than for ACTH. No ACTH and cortisol response to insulin-induced hypoglycemia and isolation-restraint stress was observed. The stimulating action of lysine-vasopressin on ACTH release was significantly reduced as compared to controls. These results indicate that CRF is a major physiological component of the ovine hypothalamo-hypophysial-adrenal axis and participates in the events that regulate ACTH and cortisol diurnal variations and response to stress.     

Effect of hyperinsulinaemia on the function of the pituitary-adrenal axis in healthy man

OBJECTIVE Circulating insulin levels in themselves have been reported to influence the counter-regulatory hormone response to hypoglycaemia in man. The effect of insulin on a specific aspect of this response was examined during euglycaemia by stimulating the pituitary-adrenal axis with human corticotrophin-releasing hormone (CRH). SUBJECTS Eight healthy males. DESIGN Following an overnight fast, insulin was infused at 15 (low) and 60 (high) mU/kg/h from 0900 h for 180 minutes on separate occasions in random order. On each occasion, blood glucose was clamped at euglycaemia, and 1 μ/kg/kg (i.v. bolus) human CRH was administered at 120 minutes. MEASUREMENTS Circulating hormone concentrations were determined by radioimmunoassay. Peak Cortisol and ACTH responses were compared for the two study conditions. RESULTS Mean serum insulin levels were threefold higher during the high compared with the low insulin infusion (mean difference 320 pmol/l, 95% confidence interval (CI) 150-490, P<0001). Blood glucose levels during the clamps were comparable (mean difference 0 15 mmol/l, 95% CI 0-0.63). Plasma Cortisol levels increased following CRH, although the peak concentration was significantly lower during the high insulin infusion (mean difference 36 nmol/l, CI 0-110, P< 0.02). However, peak ACTH levels were comparable for the two insulin levels (mean difference 8 ng/l (1.8 pmol/l), CI 0-50). CONCLUSIONS The peak Cortisol response to CRH was diminished at the higher circulating insulin levels. This was not dependent upon concurrent hypoglycaemia and did not appear to be mediated at the level of the pituitary gland.     

Effect of adrenalectomy or long term cortisol or adrenocorticotropin (ACTH)-releasing factor infusion on the concentration and molecular weight distribution of ACTH in fetal sheep plasma.

It is unclear whether the maturation of corticotrophs from the fetal to the adult type in the fetal sheep pituitary in late gestation is associated with changes in the sensitivity of the fetal pituitary to corticotrophic secretagogues and in the form of ACTH-containing peptides (IR-ACTH) secreted into the circulation. The maturation of the pituitary corticotroph population is known to be accelerated by intrafetal cortisol infusion and delayed by bilateral fetal adrenalectomy. We have therefore investigated the mol wt profile of IR-ACTH present in fetal sheep plasma from 110 days gestation until term (147 +/- 3 days) and determined whether intrafetal cortisol infusion between 105-117 days (2.5 mg cortisol/day), or bilateral fetal adrenalectomy can alter the mol wt profile of IR-ACTH in fetal sheep plasma. We have also investigated whether prior exposure to cortisol alters the subsequent responsiveness of the fetal pituitary to a long term infusion of ovine (o) CRF (10 micrograms oCRF/day). In the control group, the proportion of IR-ACTH which eluted in the low-mol wt (LMW) range (i.e. less than 12K) was significantly higher between 121-125 days (43.9 +/- 4.2%) than between 126-139 days (26.8 +/- 9.3%) but not different to that after 140 days gestation (29.9 +/- 5.5%). Between 110-117 days, cortisol infusion had no effect on the proportion of IR-ACTH in the LMW range (43.9 +/- 5.7%, saline infused; 44.1 +/- 2.4%, cortisol infused). Between 121-125 days, the proportion of IR-ACTH in the LMW range in the CRF-infused groups (with or without prior exposure to cortisol) was significantly lower (27.4 +/- 2.1%) than in the saline-infused control group. In contrast, after fetal adrenalectomy, the proportion of IR-ACTH in the LMW range between 126-139 days was significantly higher (48.0 +/- 6.7%) than in intact control animals (23.8 +/- 3.5%). We conclude that the change in the mol wt profile of IR-ACTH in fetal plasma after 125 days may be a consequence of changes in the morphological and/or functional characteristics of the corticotrophic cells in the fetal pituitary. Infusion of oCRF appears to accelerate the normal maturation of the fetal pituitary-adrenal relationship, and oCRF acting either directly or via secretion of cortisol may play a role in the posttranslational processing of POMC in the fetal sheep pituitary after 125 days gestation.     

Effect of metyrapone on the pituitary-adrenal axis in depression: relation to dexamethasone suppressor status.

It has been suggested that the well-documented hypercortisolaemia found in a proportion of patients with severe depression occurs either in response to excessive secretion of corticotrophin-releasing hormone-41 (CRH-41) from the hypothalamus, or as a consequence of up-regulation of pituitary CRH-41 receptors. The attenuation of the normal ACTH response to CRH-41 in these subjects is thought to result from inhibition of corticotrophin secretion by elevated cortisol levels. We tested these hypotheses by examining ACTH responses to metyrapone, an 11 beta-hydroxylase inhibitor which blocks the formation of cortisol, followed by CRH-41 in 15 severely depressed in-patients diagnosed according to DSM-IIIR criteria. Patients were assigned to two groups according to their response to overnight administration of 1 mg dexamethasone: suppressors (8) and nonsuppressors (7). A third group consisted of 6 healthy matched controls. Metyrapone 750 mg was given 4-hourly for 24 h and samples were taken for cortisol and ACTH. Six of the original 15 patients (3 from each group) were given a bolus dose of 100 micrograms human CRH-41 intravenously after 24 h of metyrapone, and ACTH levels were measured over 2 h. Falls in circulating cortisol in response to metyrapone were similar in all three groups. However, we found exaggerated rises in ACTH amongst the nonsuppressors, as compared to the suppressors and the control group, after metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exogenous opioid regulation of the hypothalamic-pituitary-adrenal axis in fetal sheep

To test the hypothesis that endogenous opioids participate in the regulation of the ontogenic development of the hypothalamic-pituitary-adrenal axis in fetal sheep, we measured changes in immunoreactive (ir) ACTH and cortisol concentrations in response to bolus injections of either the [Met]-enkephalin analogue, [D-Ala2,N-Phe4,Met(0)ol5]-enkephalin (FK 33-824; 25 micrograms), the opioid antagonist naloxone (1 mg), a combination of both, or saline vehicle, administered to chronically catheterized fetal sheep through late gestation. There were no effects of either FK 33-824, naloxone or saline on the release of ir-ACTH and cortisol at the earliest stage of gestation studied (days 110-115). By days 125-130, FK 33-824 caused a rapid but short-lived (30 min) increase in plasma ir-ACTH (P less than 0.05) which was accompanied by a smaller but nonsignificant increase in cortisol. Naloxone given concurrently with FK 33-824 abolished this response, thus providing evidence for a specific effect through opioid receptors. Naloxone given alone was without effect. At days 135-140, FK 33-824 caused a significant increase in ir-ACTH which was of similar duration and magnitude to that which occurred at days 125-130. There was a larger basal variation in plasma concentrations of cortisol than at days, 125-130, and a greater increase in cortisol after FK 33-824, although this did not reach statistical significance. Naloxone again reversed the effects of FK 33-824 but was without effect when given alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of chronic active immunization with antiarginine vasopressin on pituitary-adrenal function in sheep.

ACTH and cortisol diurnal variations and responses to two types of stress (insulin-induced hypoglycemia and isolation-restraint stress) and to an acute injection of CRF were determined in intact as well as in actively antiarginine vasopressin (AVP)-immunized rams. All immunized sheep developed antibodies to AVP, displayed diabetes insipidus, and looked healthy in spite of their lower gain weight. Basal secretion and diurnal variations of ACTH and cortisol were unaltered in the group of anti-AVP-immunized animals. In contrast, ACTH and cortisol responses to both types of stress and CRF injection were significantly reduced compared to those in controls. These results suggest that endogenous AVP plays a physiological role in the corticotropic response to stress. However, endogenous AVP does not appear to affect basal secretion and diurnal variations of ACTH and cortisol.     

Influence of cortisol on adipose tissue development in the fetal sheep during late gestation

The present study examined the extent to which the late gestation rise in fetal plasma cortisol influenced adipose tIssue development in the fetus. The effect of cortisol on the abundance of adipose tIssue mitochondrial proteins on both the inner (i.e. uncoupling protein (UCP)1) and outer (i.e. voltage-dependent anion channel (VDAC)) mitochondrial membrane, together with the long and short forms of the prolactin receptor (PRLR) protein and leptin mRNA was determined. Perirenal adipose tIssue was sampled from ovine fetuses to which (i) cortisol (2-3 mg/day for 5 days) or saline was infused up to 127-130 days of gestation, and (ii) adrenalectomised and intact controls at between 142 and 145 days of gestation (term=148 days). UCP1 protein abundance was significantly lower in adrenalectomised fetuses compared with age-matched controls, and UCP1 was increased by cortisol infusion and with gestational age. Adrenalectomy reduced the concentration of the long form of PRLR, although this effect was only significant for the highest molecular weight isoform. In contrast, neither the short form of PRLR, VDAC protein abundance or leptin mRNA expression was significantly affected by gestational age or cortisol status. Fetal plasma triiodothyronine concentrations were increased by cortisol and with gestational age, an affect abolished by adrenalectomy. When all treatment groups were combined, both plasma cortisol and triiodothyronine concentrations were positively correlated with UCP1 protein abundance. In conclusion, an intact adrenal is necessary for the late gestation rise in UCP1 protein abundance but cortisol does not appear to have a major stimulatory role in promoting leptin expression in fetal adipose tIssue. It remains to be established whether effects on UCP1 protein are directly regulated by cortisol alone or mediated by other anabolic fetal hormones such as triiodothyronine.     

The effect of cyproterone acetate on the pituitary-adrenal axis in hirsute women.

The functioning of the hypothalamo-pituitary-adrenal axis was assessed in 10 adult women with idiopathic hirsutism treated for 2 weeks with the anti-androgen cyproterone acetate in a dose of 50 mg b. d. daily and in 4 patients treated for at least 3 months. Basal plasma ACTH and cortisol levels and the cortisol response to 8 h ACTH infusion were comparable before and during short-term treatment. The plasma ACTH and cortisol responses to insulin induced hypoglycaemia before and during anti-androgen therapy also were of the same order of magnitude. In the 4 patients treated for at least 3 months also no suppressive effect of the anti-androgen on basal plasma cortisol levels was observed. From these data the conclusion seems warranted that short-term cyproterone acetate treatment in the given dose not significantly influences pituitary-adrenal function in adult women with idiopathic hirsutism.     

Handling during pregnancy in the blue fox (Alopex lagopus): the influence on the fetal pituitary-adrenal axis

Previous studies revealed that handling is a stressor for farmed blue foxes. The present study was designed to examine the effects of a 1-min daily handling stress applied to pregnant blue fox vixens on the function of the fetal pituitary-adrenal system. Plasma concentrations of adrenocorticotropin hormone (ACTH), cortisol, and progesterone, adrenal content of cortisol and progesterone, in vitro adrenal production of these steroids and response to ACTH, and adrenal weights were measured in control (C; n = 73) and stressed (S; n = 58) fetuses. The ACTH levels were lower in stressed fetuses than in the controls (C: males, 128.6 +/- 6.1 pg/ml; females, 165.9 +/- 6.1 pg/ml; S: males, 122.3 +/- 5.4 pg/ml; females, 145.0 +/- 8.1 pg/ml; P < 0.05). In contrast, increased plasma cortisol concentrations in both sexes were demonstrated in stressed compared with control fetuses (C: males, 9.2 +/- 0.4 ng/ml; females, 9.2 +/- 0.4 ng/ml; S: males, 11.8 +/- 0.7 ng/ml; females, 13.2 +/- 0.7 ng/ml; P < 0.00001). The same difference was observed in plasma progesterone concentrations (C: males, 1.54 +/- 0.07 ng/ml; females, 1.49 +/- 0.10 ng/ml; S: males, 1.86 +/- 0.11 ng/ml; females, 1.74 +/- 0.10 ng/ml; P < 0.01). Prenatal stress did not change the baseline adrenal production of cortisol but prevented the cortisol response to ACTH in female fetuses and decreased the progesterone production in both sexes. Additionally, prenatally stressed fetuses of both sexes had significantly lower adrenal weights than controls (C: males, 9.4 +/- 0.3 mg; females, 9.5 +/- 0.4 mg; S: males, 8.1 +/- 0.3 mg; females, 8.2 +/- 0.4 mg; P < 0.001). These results indicate that prenatal handling stress induces a dysregulation of the pituitary-adrenal axis in the fetus and suggest that increased plasma glucocorticoids in the stressed dam can cross the placenta and influence the fetal hypothalamicpituitary-adrenal axis.