Role Of ACTH Research Articles

Comparative study of the roles of ACTH and β-endorphin in regulating conditioned reflex activity in the hedgehog

Data on the relative effects of the neurohormone ACTH1-39 and the opioid peptide beta-endorphin on conditioned reflex activity in the hedgehog are presented. It was demonstrated that administration of ACTH (30-50 micrograms/kg s.c.) led to facilitation of learning and strengthening of memory processes (conditioned reflex traces). ACTH promoted strengthening of movement, orientational-investigative, and intersignal activities, produced hyperalgesia, and blocked the effects of naloxone. Administration of beta-endorphin (30-40 micrograms/kg s.c.) lengthened the latent periods of conditioned reflexes, produced a pronounced analgesic effect, and reduced movement and intersignal activities. The effects of beta-endorphin were eliminated by dosage with naloxone. Administration of beta-endorphin blocked the inhibitor effects of stimulation of the limbic cortex; doses of ACTH produced partial release of inhibitory effects. The differences between the effects of ACTH and beta-endorphin on higher nervous activity are discussed, as are the possible mechanisms of these effects.

Functional maturation of the primate fetal adrenal in vivo. II. Ontogeny of corticosteroid synthesis is dependent upon specific zonal expression of 3 beta-hydroxysteroid dehydrogenase/isomerase.

Cortisol, produced by the primate fetal adrenal, regulates the maturation of organ systems necessary for extrauterine life. During most of primate pregnancy, however, the fetal adrenal lacks the enzyme 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD), which is essential for cortisol synthesis. Therefore, we used immunohistochemistry and in situ hybridization techniques to investigate the developmental expression of 3 beta HSD in the fetal rhesus monkey adrenal from 109 days' gestation until term (165 +/- 5 days) and assessed the role of ACTH in the induction of its expression and localization. We also examined whether ACTH regulates the expression of two other steroidogenic enzymes, cytochrome P450 cholesterol side-chain cleavage (P450scc) and P450 17 alpha-hydroxylase, 17/20-lyase (P450c17), in the fetal rhesus monkey adrenal. To stimulate ACTH secretion from the fetal pituitary in vivo, we administered metyrapone to late gestation fetal rhesus monkeys for 3-7 days. Adrenals were collected from untreated fetuses at 109-125 days (n = 5), 130-148 days (n = 7), 155-172 days (n = 4), and after metyrapone treatment at 135-137 days (n = 4). The cortical width and total amount of 3 beta HSD staining were measured using an image analysis system. 3 beta HSD was localized primarily in the definitive zone cells of the adrenal from fetuses between 109-148 days, whereas at term (155-172 days), 3 beta HSD was localized in both definitive and transitional zone cells. The cortical width and total amount of 3 beta HSD staining in the adrenal increased significantly (P < 0.05) between 148 days (137 +/- 14 microns and 3,689 +/- 522 grains) and 155 days (315 +/- 61 microns and 7,321 +/- 2,008 grains). Interestingly, in metyrapone-treated fetuses at 135-137 days, 3 beta HSD messenger RNA (mRNA) and protein were localized extensively in both the definitive and transitional zones, a pattern seen only in term fetal adrenals in untreated animals. In addition, metyrapone treatment significantly (P < 0.05) increased cortical width (386 +/- 95 microns) and total 3 beta HSD immunostaining (29,063 +/- 13,692 grains) compared with age-matched controls. In contrast to 3 beta HSD, P450scc mRNA was detected in the definitive, transitional, and fetal zones, and its expression was not altered after metyrapone treatment. P450c17 mRNA was detected in the transitional and fetal zones, and the relative abundance was greater in the transitional zone. The relative abundance of P450c17 mRNA was increased in the fetal zone after metyrapone treatment. In summary, at term or after metyrapone treatment, expression of 3 beta HSD is induced in the transitional zone of the fetal rhesus monkey adrenal gland, an indication of functional maturation of the primate adrenal cortex. These data suggest that the ontogenetic increase in fetal pituitary ACTH secretion plays an important role in the induction of 3 beta HSD expression in the transitional zone.

Regulation of guinea pig adrenal P450c21 messenger RNA, protein and activity by RU486

The role of ACTH, forskolin and 8Br-cAMP on the regulation of mRNA abundance, protein levels and enzymatic activity of cytochrome P450 21-hydroxylase (P450c21, CYP21) were investigated in guinea pig adrenal cell cultures. In untreated cells, 21-hydroxylase activity was diminished throughout a 48 h period of incubation. Although incubation with forskolin and 8Br-cAMP restored 21-hydroxylase activity to normal levels, the addition of ACTH did not prevent the decrease of 21-hydroxylase activity. Treatment of cells with RU486 for 24 h inhibited 21-hydroxylase activity by 93%; however, after removal of the drug a slight increase of enzyme activity was observed; this rise was enhanced by the addition of ACTH. Forskolin and 8Br-cAMP increased the levels of 21-hydroxylase activity to the same range as seen in untreated cells. In cells that were not pretreated with RU486, incubation with cycloheximide for 1 h had no effect on 21-hydroxylase activity and could not prevent the modest increase of 21-hydroxylase activity induced by forskolin or 8Br-cAMP after 48 h of incubation. In RU486-treated cells, cycloheximide blocks the stimulation of enzyme activity induced by ACTH, forskolin and 8Br-cAMP. Our findings indicate that 21-hydroxylase activity can be stimulated by ACTH, forskolin or 8Br-cAMP solely in the presence of reduced enzymatic activity. Western immunoblot analysis of P450c21 protein levels in untreated or RU486-treated adrenal cells indicate that P450c21 protein levels were in the same range and further incubation with ACTH caused a similar elevation of P450c21 protein levels in both the untreated and RU486-treated cells. Northern blot analysis on RNA isolated from adrenal cells showed that RU486 did not alter the basal steady state levels of P450c21 mRNA. As well, incubation with ACTH or 8Br-cAMP increased the levels of P450c21 transcript to the same extent in both untreated and RU486-treated cells. These results taken together provide additional evidence for the presence of an adrenal specific protein factor(s) modulating 21-hydroxylase activity.

ACTH Effects on Aldosterone, Cortisol, and Other Steroids

The role of ACTH in the regulation of mineralocorticoid synthesis and secretion is complex. In zona glomerulosa cells, its effect is powerful but transient and ultimately negative. Its inhibitory effect on aldosterone may be mediated indirectly by its positive effect on cortisol synthesis. In zona fasciculata cells, ACTH is a major regulator of mineralocorticoid biosynthesis.

Role of ACTH in recovery from retrograde amnesia induced by hypothermia in rats.

Role of ACTH in recovery from retrograde amnesia induced by hypothermia in rats.

Role of ACTH in recovery from retrograde amnesia induced by hypothermia in rats.

The present investigation assessed whether increased congruency between ACTH state present shortly after training and that at testing contributed to memory recovery. If recovery were related to an increased correspondence between internal state present after training and that at testing, then suppressing ACTH release should block memory recovery. This was the hypothesis that was examined in the present investigation. Specifically, animals were trained on a passive avoidance task, administered hypothermia (the amnestic agent) and, shortly prior to testing, given treatments known to be effective in reversing memory loss induced by hypothermia. Before training (Experiment 1) or testing (Experiment 2) animals were injected with either dexamethasone (an agent that suppresses ACTH release) or saline. Results, in general, indicated that when ACTH release was suppressed, a blunted recovery effect was obtained. This reduction in the extent of memory recovery was observed when ACTH was suppressed either at training or at testing. These data are interpreted as providing support for an ACTH-related, state-dependent retention mechanism contributing to recovery from hypothermia-induced retrograde amnesia in rats.

Immunocytochemical localization of ACTH-like immunoreactivity in rat adrenal glomerulosa and fasciculata cells

The role of ACTH in the synthesis of the adrenocortical hormones has been largely described. In order to investigate the localization of this peptide at the subcellular level of the adrenal glomerulosa and fasciculata cells, an immunocytological method was used. Rat adrenals were fixed and frozen. Ultrathin sections obtained by cryoultramicrotomy, were incubated with anti-beta (1-24) ACTH or anti-alpha (17-39) ACTH sera. The antigen-antibody reaction was detected by PAP complexes (revealed by 4-chloro-1-naphthol) or with protein A-colloidal gold or IgG-colloidal gold. The results obtained were the same whatever the antisera of the technique employed. All the cells of the adrenal zona glomerulosa and zona fasciculata were labelled. ACTH-like immunoreactivity in zona glomerulosa and zona fasciculata cells was observed at the plasma membrane level, in cytoplasmic matrix, mitochondria and nucleus (in the euchromatin close to the heterochromatin aggregations and, occasionally, associated with the nucleolus). No immunoreactivity was observed when non-immune serum or anti-ACTH serum preincubated with ACTH were used, nor there was any modification of the immunocytochemical reaction when anti-ACTH serum incubated with heterologous antigens was employed. These data, demonstrate the presence of endogenous ACTH in both adrenal glomerulosa and fasciculata cells, and suggest that the peptide is internalized after binding to the plasma membrane.

The Role of Adrenocorticotropin in the Cortisol and Aldosterone Responses to Angiotensin II in Conscious Dogs*

The role of ACTH in the cortisol and aldosterone responses to iv angiotensin II (AII) infusion, (5, 10, and 20 ng kg-1 min-1) in dogs was evaluated by examining the effect of AII infusion in conscious dogs pretreated with dexamethasone to suppress endogenous ACTH secretion. AII infusion in untreated dogs produced dose-related increases in plasma cortisol and aldosterone concentrations. The plasma ACTH concentration also increased. Dexamethasone treatment lowered the basal cortisol concentration from 1.7 +/- 0.1 to 0.7 +/- 0.1 micrograms/dl (P less than 0.05) and the ACTH concentration from 52 +/- 3 to 41 +/- 4 pg/ml (P less than 0.05), and abolished the cortisol response to all doses of AII, indicating that ACTH was necessary for the response. On the other hand, the basal aldosterone concentration was not significantly affected by dexamethasone, although the aldosterone response to the highest dose of AII was reduced. Additional experiments were performed to determine if the cortisol and aldosterone responses to AII (20 ng kg-1 min-1) in dexamethasone-treated dogs are restored if the ACTH concentration is maintained near control levels by iv infusion of synthetic alpha ACTH-(1-24) (0.3 ng kg-1 min-1). AII still failed to increase the plasma cortisol concentration in this group of dogs; however, the aldosterone response was fully restored. To evaluate the effect of elevated ACTH levels on the steroidogenic effects of AII, dogs were treated with dexamethasone and a higher dose of ACTH (0.4 ng kg-1 min-1). This dose of ACTH increased the plasma cortisol concentration from 1.7 +/- 0.1 to 3.5 +/- 0.8 micrograms/dl (P less than 0.05), but did not significantly affect the plasma aldosterone concentration. In the presence of constant elevated levels of ACTH, AII (10 and 20 ng kg-1 min-1) increased the plasma cortisol concentration in dexamethasone-treated dogs, although the response to the 10 ng kg-1 min-1 dose was smaller than the response in untreated dogs. Infusion of AII at 5 ng kg-1 min-1 did not increase the plasma cortisol concentration. In contrast, the increased plasma aldosterone produced by AII infusion in dexamethasone-treated dogs was not altered in the presence of elevated ACTH levels. Finally, AII infusion did not alter the clearance of cortisol. Collectively, these results demonstrate that an increase in plasma ACTH is necessary for the cortisol response to AII infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma catecholamines after insulin hypoglycemia in Sheehan's syndrome.

The plasma catecholamine response to hypoglycemia was studied in a group of hypopituitary patients with Sheehan's syndrome before (group A) and after (group B) combined cortisol and thyroid hormone treatment as well as in a group of normal women (group C). The mean basal plasma norepinephrine (NE) level was significantly increased in group A compared to levels in groups B and C, in which values were similar. The mean basal plasma epinephrine (E) level was not significantly altered by hypopituitarism. The plasma NE response to hypoglycemia was similar in the three groups, while the plasma E response was blunted in groups A and B. However, the plasma E response was significantly decreased only in half of the patients. The basal E/NE ratio was similar in the three groups, but it was significantly decreased in groups A and B compared to that in group C at the peak. From these data we conclude that 1) hypopituitarism is characterized in the basal state by increased adrenergic tone, probably related to secondary hypothyroidism; and 2) during hypoglycemia adrenal stimulation is impaired only in some patients. The role of ACTH in the regulation of E secretion is minor. Impaired neurogenic regulation in some patients with Sheehan's syndrome could contribute to their illness.

The role of ACTH in placental steroidogenesis

We have studied the possible function of the placental adrenocorticotrophic hormone-(ACTH-) like substance (PALS) in placental steroidogenesis by measuring oestradiol (E2) and progesterone (P4) in term human placental explants incubated with commercially available porcine ACTH I-39. There was a dose-dependent increase in the E2 and P4 released into the medium at 24 h as compared to controls. At 48 h, no significant effect was noted. Propranolol (10(-5) M) did not block the effect of ACTH on P4 release. The data suggest that ACTH may have a regulatory role on placental steroidogenesis. The possible mechanisms of action of PALS on the placenta and the adrenal are discussed, and the role of PALS in the maintenance of pregnancy and in maternal response to stress is suggested.

Serum Zinc Levels During Oral Glucocorticoid Therapy

The course of serum zinc (S-Zn), plasma albumin (P-Alb), urinary zinc, serum alkaline phosphatase, and plasma alpha 2-macroglobulin levels was monitored in 14 adult hospitalized patients receiving oral glucocorticoid therapy, about 40-50 mg prednisone daily for various skin diseases. Within 3 days S-Zn decreased slightly from 12.6 +/- 2.3 mumol/liter (mean +/- SEM) to 11.1 +/- 2.5 mumol/liter. Then the level rose to about 14-15 mumol/liter and remained elevated, but within the normal range for the next 2 weeks. The P-Alb level showed parallel fluctuations although less pronounced. The S-Zn/P-Alb ratio increased from 0.024-0.029. No consistent patterns could be seen in the fluctuations occurring in the additional parameters studied. The possible role of ACTH on the S-Zn regulation is discussed.

The role of ACTH in determining the metabolic pathways of deoxycorticosterone by newborn rat adrenal cells in primary culture

The metabolism of deoxycorticosterone (DOC) by newborn rat adrenal cells in primary culture at various times after culture, with and without ACTH, was studied. After 5 days in culture before addition of ACTH, the main products of the metabolism of DOC were corticosterone and 18-hydroxy-11-deoxycorticosterone in a 2:1 ratio. Smaller amounts of 20α-dihydrocorticosterone and 18-hydroxycorticosterone were also found. No reduced metabolites of DOC were detected. Without ACTH the conversion of DOC to corticosterone and 18-hydroxyDOC declined rapidly. After 13 days in culture, this conversion accounted for only half the metabolites. The reductive metabolism of DOC which yields products reduced at 20α and/or 3α/β and 5α accounted for the other half. When ACTH (22 mU/ml) was added to the culture daily for several weeks, the primary metabolism of DOC remained that of 11βand 18-hydroxylation yielding corticosterone and 18-hydroxyDOC. A minor reductive metabolism was found. Both cultures produced 6β-hydroxyDOC. These results demonstrate that ACTH is needed to maintain the efficiency of the 11β/18-hydroxylating system. They also show that ACTH controls the type of metabolism predominant in the rat adrenal cell and may be responsible for the balance between the biosynthesis of glucocorticoids and their reductive catabolism in the fasciculata zone of the adrenal gland.

Adrenocorticotropin regulates angiotensin II receptors in bovine adrenal cells in vitro

The role of ACTH-(1–24) on angiotensin II receptors has been studied in bovine adrenal glomerulosa cells in primary culture. Angiotensin II receptors were measured in cells pretreated or not by ACTH-(1–24) on day 4 of culture. ACTH-(1–24) decreased angiotensin II binding sites in a time and a dose-dependent manner. After 24 hours of treatment the minimal effective dose of ACTH-(1–24) was 10 −11M and the maximal effect was obtained with 10 −8M. Moreover, ACTH-(1–24) 10 −8M decreased significantly angiotensin II receptors after 6 hours of treatment. Scatchard plot analysis showed that ACTH-(1–24) treatment did not modify the affinity of angiotensin II receptors (Ka = 0.42 and 0.44 × 10 9M −1 in control and treated cells respectively) but reduced by about half the number of angiotensin II sites per cell. Like ACTH-(1–24), 8-Bromo-cAMP, forskolin and cholera toxin decreased angiotensin II receptors. Factors such as prolactin, somatostatin, ACTH-(11–24) and dopamine which are bound to adrenal membranes without increasing cAMP production had no effect. In conclusion, these studies in vitro demonstrate for the first time that ACTH decreases angiotensin II receptors by a direct mechanism acting on glomerulosa cells, and they also suggest that this effect could be mediated by cAMP.

The effect of adrenocorticotropin or hydrocortisone on serum luteinizing hormone concentrations after adrenalectomy and/or ovariectomy in the prepuberal gilt.

The possible role of ACTH and the adrenal gland in modulating LH secretion in prepuberal gilts was studied. Fifty-one gilts, 170-175 days of age, were randomly assigned to 12 treatments in a 2 X 2 X 3 factorial design. The main treatments were adrenalectomy (ADX) or sham-ADX, ovariectomy (OVX) or sham-OVX, and ACTH, hydrocortisone acetate (HCA), or vehicle (V) administration. ACTH, HCA, or V was administered from days 3-10 after surgery. Beginning at 0800 h on day 10, blood samples were collected every 15 min for 16 h via jugular cannulae. At 1600 and 2000 h, all gilts were injected iv with a pharmacological dosage of 400 micrograms GnRH. ADX and OVX did not influence subsequent serum cortisol (CS) concentrations, detected by RIA. HCA elevated serum CS concentrations in all four surgical groups. ACTH treatment elevated serum CS and progesterone concentrations only in the sham-ADX groups. Every 3 days after surgery, all ADX gilts received 10 mg deoxycorticosterone acetate, im, as an electrolyte maintenance treatment, which may have been detected in the peripheral blood by the CS assay since the cross-reaction of deoxycorticosterone with the first antibody of the CS assay was 17.1%. Serum LH concentration, peak frequency, and peak magnitude were greater in V-treated OVX gilts than in V-treated sham-OVX gilts in both ADX and sham-ADX groups. Chronic ACTH treatment blocked the increase in basal serum LH concentration, peak frequency, and peak magnitude after OVX only when the adrenal glands were present. In contrast, HCA blocked the postcastration increase in the basal serum LH concentration and peak magnitude in the presence or absence of the adrenal glands. However, HCA had no effect on the increased frequency of LH peaks that occurred after OVX in V-treated gilts. The serum LH responses after both GnRH challenges were similar for all gilts, and the LH response to the second GnRH challenge was less than that observed after the first challenge. These data indicate that ACTH and HCA suppressed the postcastration increase in LH secretion. However, the effect of ACTH was mediated through the adrenal gland, and the inhibiting influence of ACTH and HCA on LH secretion was apparently not mediated at the pituitary level in the prepuberal gilt.

Memory as a state dependent phenomenon: Role of ACTH and epinephrine

Rats received an ip injection of saline, epinephrine HCl (5.0 micrograms/kg), or ACTH1--24(0.2 microgram/kg) immediately after training in a step-down inhibitory avoidance task, and an ip injection of saline, or epinephrine (0.5, 1.0, 2.0, 3.0, 5.0, or 10.0 mu/kg), or ACTH (0.02, 0.04 0.08, 0.12, 0.2, or 0.4 microgram/kg) 6 min prior to a test session of the same task 24 hr after training. Retention was excellent in the groups treated with saline after training, and poor in those treated with ACTH or epinephrine after training and tested under saline. The amnestic effect of the drugs was counteracted by their administration prior to testing, and there was a dose-response curve for this effect: partial recovery from amnesia was obtained with 20 or 40% of the amnestic dose and full recovery was obtained with 60 to 100% of that dose when the same drug was given after training and prior to testing; if the drugs given after training and prior to testing were not the same, full recovery was obtained only with twice the amnestic dose of the latter. These findings are consistent with the hypothesis that learning depends on the relation between the endogenous levels of these two hormones in the post-training period and during testing. The animals seem capable of discriminating between the two drugs only partially.

Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland.

A model proposed for regulation of steroidogenesis, lipoprotein utilization and cholesterol metabolism in HFA tissue is presented in Fig 17. We envision that the role of ACTH and cAMP in steroidogenesis and cholesterol metabolism is as follows. ACTH binds to specific receptors on the surface of the cells of the HFA gland and as a consequence, adenylate cyclase is activated, leading to increased formation of cAMP. cAMP causes activation of protein kinase that leads, presumably, to phosphorylation of specific proteins. This leads to the initiation of reactions that give rise to increased activity of key enzymes and levels of proteins involved in adrenal cholesterol metabolism. Presumably, the action of ACTH causes an increase in the activity of cholesterol side chain cleavage, the rate-limiting step in the conversion of cholesterol to steroid hormones. We suggest that once the mitochondrial cholesterol side-chain cleavage system is fully activated by ACTH, the supply of cholesterol to the mitochondria becomes rate-limiting for steroidogenesis. To meet this demand for cholesterol, a further action of ACTH results in an increase in the number of LDL receptors. LDL binds to specific receptors on the cell surface that are localized in coated pits. LDL is internalized by a process of adsorptive endocytosis and the internalized vesicles fuse with lysosomes and the protein component of LDL is hydrolyzed by lysosomal proteolytic enzymes to amino acids. The cholesteryl esters of LDL also are hydrolyzed to give rise to fatty acids and cholesterol. The liberated cholesterol is available for utilization in the biosynthesis of steroid hormones and other cellular processes. In addition, ACTH stimulates the activity of HMG CoA reductase and, thus, the rate of de novo cholesterol biosynthesis. In this way sufficient cholesterol is obtained to provide for precursor cholesterol to maintain the high rate of steroid synthesis by the HFA. HDL is not utilized as a source of cholesterol by the HFA. Because of the rapid rate of utilization of LDL by the HFA, fetal plasma levels of LDL are low and the activity of the HFA is a primary determinant of these levels. Thus, in the case of anencephaly, in which the activity of the adrenal is very low, plasma levels of LDL are 2--3 times higher than in normal fetuses, whereas plasma HDL levels are similar. In addition, in the normal neonate plasma LDL levels rise rapidly after birth, and this event is coincident with the involution of the fetal zone of the adrenal. The fetal liver is likely to be the major source ultimately of the LDL-cholesterol utilized by the HFA. Consequently, factors that regulate cholesterol and lipoprotein synthesis in the fetal liver may, in turn, affect the steroidogenic activity of the HFA through regulation of the supply of cholesterol precursor. Thus, if trophic factors for the HFA other than ACTH exist, an important site of their action might be the fetal liver, rather than a direct action to influence the rate of synthesis of steroids by the fetal adrenal.

Angiotensin II-induced aldosterone stimulation in man is not dependent upon adrenocorticotropin.

To document a possible role of ACTH in the aldosterone response to angiotensin II, we measured plasma aldosterone levels during physiological increments in plasma angiotensin II in normal male volunteers on two occasions, once with suppression of endogenous ACTH secretion (dexamethasone or hydrocortisone) and again without ACTH suppression. The subjects were studied under standardized conditions of dietary sodium (40 mmol/day) and potassium (100 mmol/day) intake and controlled body posture. Glucocorticoid pretreatment did not alter the plasma levels of angiotensin II attained during incremental infusions (0.5, 1, 2, and 4 ng/kg . min) of the octapeptide. Baseline plasma aldosterone levels were significantly lowered by glucocorticoid pretreatment. However, aldosterone responsiveness to infused angiotensin II (change and percentage of change from baseline levels) was not altered by suppression of endogenous ACTH production. Serum potassium levels were not increased by the administration of angiotensin II. The results demonstrate that in normal males on a sodium-restricted diet, baseline aldosterone levels are controlled in part by ACTH. The aldosterone response to angiotensin II, however, is not dependent upon endogenous ACTH secretion, an action of angiotensin II on the pituitary to release ACTH, or a rise in serum potassium.

Effect of short dexamethasone suppression on plasma steroids in prepubertal and pubertal girls.

In 40 girls aged from 2 to 14 years, subdivided into groups according to age and pubertal development, and in 6 adult female volunteers, plasma cortisol (F), pregnenolone (delta 5), dehydroepiandrosterone (DHA) progesterone (P), 17-hydroxyprogesterone (17P), androstenedione (A), testosterone (T) and estradiol (E2) were measured before and after short dexamethasone (DXM) suppression. The results confirmed the capacity of DXM to inhibit plasma steroids in all age groups, except T in 2-9 year old and P1 Tanner's stage girls. The percentage suppression of each given steroid was constant over the age groups from 6-9 years to P4-5 Tanner's stage, while lower suppression was found in 17P, P and DHA in 2-5 year old girls and in 17P, DHA and E2 in adult women. These results emphasize the fundamental role of ACTH as the overall stimulating factor of adrenal steroidogenesis but do not negate the possibility of another factor responsible for the development of the adrenal androgen secreting cells throughout prepuberty and puberty.

Role of ACTH on the cytomorphology of testes of the immature rat

The male gametogenic development of the immature rat shows inhibitory effect by the exogenous infusion of ACTH (0.25 IU and 0.50 IU; i.p.). Seminiferous tubular degeneration, Leydig cell atrophy and Sertoli cell regression are very conspicuous in the dosage of 0.50 IU ACTH (i.p.). Cytometrical and histological evidence confirms that ACTH could be inhibited by FSH during male gametogenic development which leads to cellular degeneration of testes in the immature rat.

Steroid Production by Definitive and Fetal Zones of the Human Fetal Adrenal Gland*

This study was performed to assess the relative contributions of the fetal and definitive zones of the human fetal adrenal gland to "corticoid" (cortisol and perhaps other corticosteroids) and dehydroepiandrosterone sulfate (DHAS) production, and the possible regulatory role of ACTH and the fetal pituitary in the secretion of of these steroids. Corticoid and radioimmunoassayable DHAS or total aromatizable androgen secretion by the isolated definitive and fetal zones of the human fetal adrenal gland between 10-20 weeks gestation has been studied in a superfusion system. Different functional capacities of the two zones were seen; corticoids were found to be secreted primarily by the definitive zone, while DHAS was found to be the main secretory product of the fetal zone. Addition of ACTH (250 ng/ml) or fetal pituitary homogenate produced a 2- to 5-fold stimulation of corticoid production by the definitive zone at all gestational ages studied. DHAS secretion by the fetal zone was also stimulated by ACTH. These results indicate that the definitive and fetal zones of the human fetal adrenal gland at midgestation have the capacity to respond to ACTH with increased corticoid or DHAS secretion, respectively.