C R Parker’s research while affiliated with University of Alabama at Birmingham and other places

We sought to determine the effect of maternal infections on the fetal hypothalamic-pituitary-adrenal axis. Umbilical cord blood was collected at vaginal delivery after labor (24-44 wk. gestation) from 361 infants of women having normal pregnancy ( apart from preterm delivery in some) and 110 infants of women diagnosed with infections: 86% of these women had amnionitis. Infants exposed to antenatal corticosteroids, being growth retarded, or having developmental abnormalities that would be expected to alter function of the hypothalamic-pituitary unit were excluded. Umbilical cord serum was assayed for dehydroepiandrosterone sulfate (DS) and for cortisol. The data were analyzed by use of SAS. The gestational age of the infants of normal women (35.8+/-0.2 wk., Mean +/- SE) was greater than that of the infants of women having infections (34.3+/-0.4 wk., P = 0.003). Umbilical cord serum levels of DS and cortisol rose as a function of gestational age in both groups of infants (P<0.01). Despite being, on average, 1 wk. younger than the normal infants are, the infants of women having infections during pregnancy had higher serum levels of cortisol and DS than did those infants of the normal women. These data are consistent with activation of the fetal hypothalamic-pituitary-adrenal axis in pregnancies complicated by maternal infections. Such a fetal response could be the consequence of transplacental passage of products of the activated maternal immune system.

Dehydroepiandrosterone sulfate (DS) is the major adrenal androgen produced in the fetal and adult human; its formation is dependent upon the action of dehydroepiandrosterone sulfotransferase (DST). Since the factors that regulate DST are poorly characterized, we investigated the effects of ACTH, which stimulates DS production, and the cytokines transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) , both of which are inhibitory to adrenal steroidogenesis, on cultured human fetal adrenal cells. Cellular levels of DST mRNA were increased in a dose dependent fashion in response to ACTH; DST mRNA was less responsive to ACTH stimulation than was 17 hydroxylase (CYP 17) mRNA. The stimulatory effects of ACTH on DST mRNA levels were blunted by both TGF-beta and TNF-alpha; the inhibitory effects of TNF-alpha on DST mRNA were more striking than were those on CYP 17 mRNA. These data suggest that DS production can be altered by several agents acting on the DST gene.

Administration of dehydroepiandrosterone (DHEA) to female rats produces a condition of reproductive failure and ovarian cysts similar to that seen in women having polycystic ovarian disease. On the other hand, DHEA may have beneficial effects on the immune system. We sought to determine the effect of DHEA, when administered in pharmacological amounts, on the thymus and spleen of prepubertal (25 day old) and young adult (60 day old) female rats. Since the adrenal, by means of its production of corticosteroids, also is known to modulate the immune system, we also evaluated the effects of DHEA administration on this gland. The daily SC administration of DHEA (6 mg/100g BW) to young adult female rats led to progressive and striking reductions in thymic weights (greater than 85% suppression after 20 days compared to vehicle treated animals). There were no effects of DHEA on body weights or the weights of the spleen. DHEA treatment also led to significantly reduced weights of the adrenals , which was sustained at about 15-20% below normal over 5-20 days treatment. Ovariectomy of the rats 5 days before initiation of DHEA or vehicle treatment gave rise to significant increases in thymic and spleenic weights in control animals and strikingly blunted the inhibitory effects of DHEA treatment for 10 days on the thymus; DHEA had no effect on the ovariectomy-induced rise in the weight of the spleen. Ovariectomy also had no effect on the inhibitory effects of DHEA on adrenal weight. Similar, albeit quantitatively less striking, responses were noted to occur after DHEA treatment in immature female rats. These data indicate that DHEA in doses sufficient to interfere with ovarian cyclicity also has potentially adverse effects on the adrenal and thymus. The ovary appears to play an independent role in maintenance of the size of the thymus and spleen and also may mediate some of the effects of DHEA on the thymus but not those on the adrenals.

Aging in women is associated with reduced production of adrenal androgens (AAs); this decrease may in part be the result of menopausal hypoestrogenism. To determine the effects of physiological concentrations of estradiol (E2) on adrenocortical sensitivity and responsiveness in postmenopausal women, we determined steroid responses to a continuous incremental ACTH-(1-24) infusion (0, 20, 40 80, 160, 320, 640, and 1280 ng/1.5 m2/h), followed by an ACTH-(1-24) bolus of 0.25 mg, after overnight dexamethasone suppression before and after 3 months of E2 therapy (transdermal E2, 0.05 mg/day) in 14 postmenopausal women. After E2 treatment, subjects demonstrated an increase in serum E2 concentrations from 29.8 +/- 2.6 to 49.9 +/- 6.0 pg/mL (P < 0.005) and a decline in mean FSH levels from 83.1 +/- 24.4 to 57.5 +/- 17.3 mIU/mL (P < 0.004). E2 administration had no effect on basal, postdexamethasone, or maximally stimulated serum levels of cortisol (F), dehydroepiandrosterone (DHEA), androstenedione (A4), or 17-hydroxyprogesterone (17-OHP). Furthermore, E2 did not affect adrenal sensitivity or responsiveness to ACTH-(1-24) stimulation. Finally, the steroid ratios reflecting 3 beta-hydroxysteroid dehydrogenase (i.e. the A4/DHEA ratio) and delta 417,20-lyase (i.e. the A4/17-OHP ratio) activities also were unaffected by E2 therapy. The responsiveness of F to ACTH was significantly greater than that of DHEA, A4, or 17-OHP regardless of the circulating E2 levels. Furthermore, F and A4 were significantly more sensitive to ACTH stimulation than were 17-OHP and DHEA, and this was not altered by E2 administration. We conclude that transdermal E2 replacement to postmenopausal women does not significantly alter AA sensitivity or responsiveness to ACTH. Hence, it is unlikely that the hypoestrogenism of menopause contributes to the decline in AAs noted with age. Furthermore, menopausal estrogen replacement, at least in physiological amounts administered transdermally, cannot be expected to reverse the suppressed production of these androgens.

Aging in women is associated with reduced production of adrenal androgens (AAs); this decrease may in part be the result of meno- pausal hypoestrogenism. To determine the effects of physiological concentrations of estradiol (E2) on adrenocortical sensitivity and re- sponsiveness in postmenopausal women, we determined steroid re- sponses to a continuous incremental ACTH-(1-24) infusion (0, 20, 40, 80, 160, 320, 640, and 1280 ng/1.5 m2/h), followed by an ACTH-(1-24) bolus of 0.25 mg, after overnight dexamethasone suppression before and after 3 months of E2 therapy (transdermal E2, 0.05 mg/day) in 14 postmenopausal women. After E2 treatment, subjects demonstrated an increase in serum E2 concentrations from 29.8 6 2.6 to 49.9 6 6.0 pg/mL (P , 0.005) and a decline in mean FSH levels from 83.1 6 24.4 to 57.5 6 17.3 mIU/mL (P , 0.004). E2 administration had no effect on basal, postdexamethasone, or maximally stimulated serum levels of cortisol (F), dehydroepiandrosterone (DHEA), androstenedione (A4), or 17-hydroxyprogesterone (17-OHP). Furthermore, E2 did not

Whereas aging has been shown to be associated with striking reductions in circulating levels of adrenal androgens in humans, the alteration in adrenal function that occurs in aging has not been identified. We sought to determine if there are changes in the zonation of the adrenal in aging men by performing histomorphologic analyses of adrenal specimens that had been obtained at autopsy following sudden death due to trauma. We evaluated adrenals from 21 young men (20-29 yrs) and 12 older men (54-90 yrs); inclusion criteria required the presence of medullary tissue in the specimen and fixation within the first 24 hrs postmortem. Sections stained with H/E were examined microscopically and areas of the cortex that included adjacent medullary tissue were chosen for quantitative evaluation by use of a computerized image analysis system. The average width (arbitrary units, pixels) of the zona reticularis and that of the combined zonae fasciculata/glomerulosa were determined from sections stained for reticulum fibers. The zona reticularis represented 37.1 +/- 1.9% of the total cortical width in the young men, which was significantly greater than that of the older men (27.1 +/- 3.3%, P = 0.0082). The zona fasciculata/glomerulosa to zona reticularis ratio in the young men (1.84 +/- 0.15) was significantly less that that of the older men (3.29 +/- 0.47, P = 0.0011). There was no significant difference in the total width of the cortex in young compared to older men. These data suggest that aging results in alterations within the cortex of the adrenals in men such that there is a reduction in the size of the zona reticularis and a relative increase in the outer cortical zones. A reduced mass of the zona reticularis could be responsible for the diminished production of dehydroepiandrosterone and dehydroepiandrosterone sulfate that occurs during aging.

Prior studies suggest that fetal plasma cholesterol is regulated in part by the rate of uptake and utilization of low-density lipoprotein cholesterol by the fetal adrenals for use in steroid biosynthesis. Direct evidence for this phenomenon and the kinetics of this process is, however, virtually impossible to obtain in a controlled experiment in the developing human. In the current study we sought to take advantage of the anticipated transient inhibition of the hypothalamic-pituitary-adrenal axis that occurs after antenatal therapy with glucocorticosteroids, to evaluate the temporal relationship between fetal adrenal steroids and plasma lipoprotein cholesterol levels in umbilical cord blood at delivery. Umbilical cord serum was obtained at delivery from 136 infants (30.5 +/- 2.7 weeks' gestation) who previously had been treated in utero with betamethasone, 12 mg per 12 or 24 hours for one or two doses and from 308 preterm infants (30.5 +/- 2.1 weeks) who had not been exposed to such therapy. We quantified the concentrations of dehydroepiandrosterone sulfate and cortisol as representative fetal adrenal steroids and also measured the total cholesterol and apolipoprotein B; the relationship between the steroids and lipids as a function of the interval between initial treatment and delivery was analyzed. Umbilical cord levels of dehydroepiandrosterone sulfate and cortisol were significantly reduced within the first 24 hours after initial treatment and remained significantly lower than in control infants through 4 days after initial treatment. In contrast, serum levels of cholesterol were significantly increased 3 to 4 days after treatment but fell on day 5. Serum levels of apolipoprotein B generally followed the same pattern as cholesterol. Cholesterol levels also were higher than normal in infants delivered >1 week after initial betamethasone treatment. The results of this study are consistent with the view that the plasma cholesterol pool in the fetus is regulated, at least in part, by the rate of uptake of low-density lipoprotein cholesterol and utilization by the fetal adrenals as substrate for steroidogenesis. Betamethasone also may influence cholesterol and lipoprotein synthesis in the fetus.

Our purpose was to determine whether in a low-dose aspirin trial a longitudinal decrease in maternal serum thromboxane B2 is associated with improvement in pregnancy outcomes. A total of 606 healthy nulliparous women with singleton gestations were randomized at 24 weeks to either 60 mg of aspirin or a placebo. Maternal serum thromboxane B2 was measured at randomization, at 29 to 31 weeks, at 34 to 36 weeks, and at delivery. After delivery, and without knowledge of patient outcome or group assignment, patients were categorized as having had either a longitudinal twofold or greater (> or = 50%) or less than twofold reduction (< 50%) in thromboxane B2 from baseline levels at randomization. Of 606 entrants, 92% had sufficient thromboxane B2 determinations to allow categorization. Whether patients were assigned to aspirin or placebo, birth weight was significantly greater in women who had a twofold or greater reduction in maternal serum thromboxane B2 levels. When the aspirin and placebo groups were combined, women with a twofold or greater reduction in thromboxane B2 levels had less preeclampsia, 1.9% (6/314) versus 5.7% (14/244) (p = 0.016), less preterm delivery (5.7% vs 10.7%, p = 0.032), fewer small-for-gestational-age newborns, 9 of 314 (2.95) versus 17 of 244 (7%) (p = 0.023), and a higher mean birth weight, 3314 gm versus 3121 gm (p = 0.0001). Women with a twofold or greater longitudinal reduction in maternal serum thromboxane B2 had less preeclampsia and prematurity, fewer small-for-gestational-age newborns, and higher birth weights than women with less than a twofold reduction.