Testicular and adrenocortical function in healthy men and in men with benign prostatic hyperplasia.

The influence of aging upon serum concentrations of testicular steroids, sex hormone binding globulin (SHBG) and pituitary hormones and on adrenal steroid levels and adrenal steroid response to ACTH was studied in 81 healthy men aged 20-87 years. These endocrine variables were also compared in 43 patients with benign prostatic hyperplasia (BPH), aged 58-89 years and in a subgroup of 41 men, aged 58-87 years, from the above mentioned reference population. The normal endocrine aging was characterized by a rise in SHBG levels, decreasing levels of testicular steroids and non-SHBG-bound testosterone (NST) and increasing gonadotropin levels and decreasing concentrations of total estrone. Adrenal androgen levels decreased in the presence of unchanged levels of cortisol and the adrenal steroid response to ACTH changed by decreasing increments in dehydroepiandrosterone (DHA) and increasing increments in 17 alpha-hydroxyprogesterone (17OHP). With the exception of the alterations in SHBG and adrenal androgens, all these changes were finished before the seventh decade of life. BPH patients had elevated levels of testosterone and NST in the presence of normal SHBG and gonadotropin levels, elevated levels of DHA and DHA sulfate (DHAS) in the presence of normal cortisol levels, a "younger" pattern of adrenal steroid response to ACTH as judged from the increments in DHA and 17OHP, elevated ratios between estrone and 4-androstene-3,17-dione suggesting an increased peripheral aromatization and subnormal prolactin levels. BPH patients may be considered as "endocrinologically younger" than healthy subjects. DHA and especially its proximate metabolite 5-androstene-3 beta, 17 beta-diol exert powerful estrogenic effects on the receptor level. Thus the elevated levels of DHA and DHAS in the BPH patients may create an hyperestrogenic condition in addition to the slight hyperandrogenicity caused by the elevated NST levels. Both endocrine aberrations may play a role in the etiology of BPH, in accordance with the dual sex steroid sensitivity of the periurethral glands.     

Influence of exposure to moderate altitude on the plasma concentraton of cortisol, aldosterone, renin, testosterone, and gonadotropins

The influence of 11 days at moderate altitude (2,000 m) combined with exercise on plasma concentration of testosterone, FSH (follicle-stimulating hormone), LH (luteinizing hormone), cortisol, aldosterone, and renin activity was studied in ten healthy subjects. Within 48 h of arrival at moderate altitude a significant increase in testosterone was found whereas FSH had decreased significantly and LH showed a tendency to decrease. Cortisol increased significantly at the beginning and reached a maximum at the end of altitude exposure. The plasma aldosterone level rose continuously and on the last day of altitude was significantly elevated. Plasma renin activity showed a tendency to decrease. On return to low land all measured parameters returned to base line values within 2 days. The findings of increases in plasma levels of aldosterone and testosterone (and serum T3 and T4, as reported by others) are in contrast to the previously found decrease of urinary excretion of all these hormones. This appears to be a distinct dissociation of serum levels of adrenal (and thyroid) hormones from their urinary excretion. The observed increase in plasma aldosterone is probably mediated through ACTH and the rise in plasma potassium, since plasma renin activity showed an opposite trend. The rise in plasma testosterone is probably of adrenal origin since plasma gonadotropins declined simultaneously. The increase of plasma levels of glucocorticoids, mineralocorticoids, and androgens after an ascent from 600 m to 2,000 m above sea level is compatible with an ACTH-mediated stimulation of the entire adrenal cortex and/or a diminished elimination of adrenal steroids: The concomitant fall of FSH, LH, and plasma renin would then be a consequence of a direct negative feedback inhibition of these hormones.     

An adrenocortical tumor secreting weak mineralocorticoids

An adrenocortical carcinoma (15.5 g) secreting excessive amounts of steroids with weak mineralocorticoid activity in a 25-year-old woman was studied with particular reference to its in vivo and in vitro secretions of steroids. Severe hypertension, occasional low serum potassium and suppressed PRA were the major clinical findings, and were improved with removal of the tumor. In the preoperative stage, plasma levels of 11-deoxycorticosterone, 18-hydroxy-11-deoxycorticosterone, corticosterone and 18-hydroxycorticosterone were all increased. However, the plasma level of aldosterone was repeatedly normal. Although plasma levels of pregnenolone, 17-hydroxypregnenolone, progesterone and 17-hydroxyprogesterone were very high, those of other late step steroids, i.e. 11-deoxycortisol, cortisol, dehydroepiandrosterone, androstenedione and testosterone were almost normal. From these findings, a major etiological role of weak mineralocorticoids such as 11-deoxycorticosterone, 18-hydroxycorticosterone and corticosterone in her hypertension was suggested. Pregnenolone and 17-hydroxypregnenolone in tumor tissue were increased, but 11-deoxycorticosterone, corticosterone, aldosterone, cortisol and adrenal androgens such as dehydroepiandrosterone, androstenedione and testosterone were below normal or low normal. In vitro production of 11-deoxycorticosterone, aldosterone or cortisol by the tumor tissue slices was very low and scarcely responded to synthetic ACTH.     

La puberté surrénalienne

The androgens produced by the adrenal glands are mainly Δ5 steroids, first dehydroepiandrosterone (DHA) and its sulfate (DHAS). Adrenal androgens, very high at birth, decrease rapidly the first few months of life, remaining very low from 1 to 6 years of life. Adrenarche is defined as the changes in the pattern of adrenal secretions which occur several years before the onset of gonadal puberty (gonadarche). Developmental patterns of adrenal androgens differ markedly among species and only the chimpanzee exhibits an adrenarche comparable to that of man. Adrenarche starts in both sexes around age 7. The increase in DHA/DHAS has a rather abrupt onset and is thereafter progressive. Before the onset of gonadarche mean levels of DHA and DHAS have increased by about 10 and 20 fold respectively. The prepubertal rise in plasma Δ⁵-androgens is accompanied by that of Δ4-androstenedione and 11β-hydroxy-Δ⁴-androstenedione occurring likely at about the same time but being very progressive and more modest are only significant after age 8 in both sexes. Adrenal androgens continue to rise during puberty. Plasma levels of DHA and DHAS continue to rise from pubertal stages 1 to 5 and remain similar in both sexes until age 15. At pubertal stage P5, plasma DHA levels are similar to that seen in young adults with no sex difference while that of DHAS continue to rise in boys and become significantly higher than in girls. Developmental changes in adrenal androgen secretions are also observed in the response to ACTH stimulation. Whether estimated as absolute levels or Δ of response, the rise in all unconjugated adrenal androgens to a short or prolonged ACTH stimulation, is greater with increasing age, with no sex difference, and is somewhat correlated to basal levels. Plasma levels of DHAS do not vary significantly the 2 hours following a bolus injection of ACTH (21, 34) but its response to longterm (3-days) ACTH stimulation is also increasing with age. Morphological and functional changes in the adrenal cortex also occur during development. Focal development of aZona reticularis starts at 5 years of age, and progressively becomes continuous. The development of the zona reticularis is parallel to the increase in adrenal androgen secretions, and is completed only by age 15. This is accompanied by a rise in 17-hydroxylase and 17,20-desmolase activity in the adrenals. In a normal timing of physiological events, the onset of adrenarche occurs several years before the onset of gonadarche, 2–3 years in girls and 3–4 years in boys. This relation does not preclude that the processes are independent events. Indeed, the onset of adrenarche and gonadarche are dissociated in a variety of disorders of sexual maturation Adrenal androgen secretions are under the control of ACTH, as shown by a series of observations. However, the specific increase of adrenal androgen secretions during development without any detectable change in ACTH stimulation, the dissociation between adrenarche and gonadarche in several conditions, have led to postulate that the biochemical differentiation of the zona reticularis may require the action of an «adrenal factor» in addition to ACTH. Among the proposed «trophic» factors of adrenal androgen secretion, LH/FSH and estrogens are no longer believed to be involved. The evidences for the existence of a separate and specific pituitary cortical androgen-stimulating hormone (CASH) are not yet convincing. Prolactin, linked to nutritional status, may stimulate the activity of the adrenal hydroxysteroid sulfotransferase. The functional zonal theory» is attractive, but it does not explain why changes in adrenal androgens occur at a given age. Finally, the occurrence of familial cases of premature pubarche, the study of the changes in adrenal androgens in monozygotic or dizygotic twins and the observation that in idiopathic delayed puberty the delay in adrenarche is only one part of a generalized growth and developmental delay, strongly suggests that maturation of the adrenal cortex is regulated, at least in part, by genetic factors. The physiological importance of adrenal androgens remains a matter of controversy. Classical “dogma” dictates that adrenal androgens are responsible for pubic hair development. It has also been suggested that they contribute to somatic growth or epiphyseal advancement in childhood. This is mainly based on the observation that premature adrenarche is accompanied by premature pubarche, tall stature and advanced bone age. However, adequate androgen secretion alone does not ensure normal sexual hair development in many patients with gonadal dysgenesis. Moreover, in children with a lack or delayed adrenarche long-term treatment with DHAS at dosages such as to restore normal levels for age, failed to induce growth of sexual hair or any change in growth rate, bone maturation velocity, or to advance puberty. Although new hypotheses favour the view that Δ5-androgens, particularly Δ⁵-androstenediol, have some characteristic properties of estrogens, the physiological role of adrenal androgens, if any, remains to be established. DHAS may well be only a prohormone. There are ample evidences that all tissues possess active sulfatases which transform it into DHA, a steroid with high turn-over. Administration of DHA to experimental animals has shown beneficial effects on various endocrine-metabolic parameters, enhanced immunoprotective functions and reduced carcinogenesis. DHA prevents diabetes in genetically diabetic and obese mice. The importance ofin vivo andin vitro experimental findings is underscored by epidemiological data showing that low DHA levels are correlated with increased cardiovascular morbidity in men, breast cancer in women and a decline in immune competence. Human studies are at the moment controversial. It remains possible that DHAS influence breast cancer risk earlier in life, and/or that there are more complex interactions with other hormones or the intracellular metabolism of DHA/DHAS. Indeed, the tissue concentrations of DHAS may be important since it may act indirectly via its metabolism into estradiol or other steroids. Further long-term studies are needed to conclude whether DHA/DHAS are a youth fountain.     

ADRENAL FUNCTION IN WILD AND REHABILITATED PACIFIC HARBOR SEALS (PHOCA VITULINA RICHARDII) AND IN SEALS WITH PHOCINE HERPESVIRUS-ASSOCIATED ADRENAL NECROSIS

Adrenal function in harbor seals (Phoca vitulina richardii) was evaluated using adrenocorticotrophic hormone (ACTH) stimulation tests and fecal cortisol levels. The effect of ACTH administration on plasma cortisol and aldosterone levels in five free-living and 14 rehabilitated harbor seal pups was determined using enzyme immunoassay and radioimmunoassay, respectively. In free-living seals, injection of ACTH caused a significant increase in mean plasma cortisol but not of mean aldosterone levels 60 min postinjection. In these seals, mean initial plasma aldosterone was significantly higher than initial levels in rehabilitated seals, while initial cortisol levels were similar. Of the rehabilitated seals, eight died with adrenal cortical necrosis associated with herpesvirus inclusions, while six lived to be released. In the seals that were released, both mean initial cortisol levels and response to ACTH decreased through rehabilitation. In the seals that died, mean initial cortisol and response to ACTH increased through rehabilitation. The differences between initial cortisol levels in seals that lived and those that died were significant at weeks two and four of rehabilitation but not at the week of admission. There was considerable individual variation in initial plasma aldosterone levels and responses to ACTH, although initial aldosterone levels were significantly higher in rehabilitated seals that died than in seals that lived. Seals with adrenal necrosis associated with herpesvirus infection did not have decreased adrenal hormone responses to ACTH. Differences between initial hormone levels and responses to ACTH in different groups of seals may be associated with differing stress levels. Fecal cortisol assays were not a useful method of assessing adrenal function in these seals, as measured levels did not correlate with plasma cortisol levels.     

Studies on lipoprotein and adrenal steroidogenesis: II. Utilization of low density lipoprotein- and high density lipoprotein-cholesterol for steroid production in functioning human adrenocortical adenoma cells in culture

We examined the utilization of human low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol for steroid production in primary monolayer culture cells from adenomas of primary aldosteronism and Cushing's syndrome and an adrenal of nodular hyperplasia of Cushing's syndrome. We compared the data obtained with findings in the case of cultured normal human adrenocortical cells. In the presence of 10(-7) M adrenocorticotropin (ACTH), the addition of either LDL or HDL to the culture medium at a cholesterol concentration of 100 micrograms/ml led to a significant increase in the daily secretion rates of cortisol, dehydroepiandrosterone sulfate (DHEA-S) and aldosterone in the adenoma and nodular hyperplasia cells, as in the normal cells. Although LDL greatly increased the secretion of steroid hormones, no significant difference in steroid secretion following the treatments with LDL and HDL were observed in these cultured cells. The contribution of endogenous cholesterol to steroid production was also high, thereby indicating that the neoplastic transformation did not have untoward effects. Cells from adenomas of primary aldosteronism secreted not only aldosterone, but also cortisol and DHEA-S. The daily secretion rates of these steroids were markedly increased when ACTH was added to the medium. With prolonged exposure to ACTH, however, the rate of aldosterone secretion showed a gradual decrease with the incubation time. This decrease might be due to the impaired conversion of corticosterone to 18-hydroxycorticosterone. In case of adenomas in patients with Cushing's syndrome, the secretion of steroid hormones varied in quantity and quality, depending on the type of plasma cortisol response to the rapid ACTH test in vivo, thereby suggesting that the adrenocortical adenoma of Cushing's syndrome might be divided into two subtypes. These results indicate that human functioning adrenocortical adenoma cells utilize plasma lipoproteins as a source of cholesterol for steroidogenesis during the prolonged stimulation of steroid secretion.     

Effect of acute ACTH administration on plasma steroid levels in the dog

Production of adrenal steroids in intact and castrated dogs is stimulated acutely by ACTH. While the increase in plasma cortisol, 17-hydroxypregnenolone and 17-hydroxyprogesterone is not affected by castration, the increment of dehydroepiandrosterone is totally abolished. On the other hand, administration of 17-hydroxypregnenolone in adrenalectomized dogs caused an increase in plasma C-19 steroids such as dehydroepiandrosterone, androstenedione and testosterone indicating that this C-21 progestin in plasma is rapidly converted. The site of this conversion is likely the testis. Furthermore, acute hCG administration in adrenalectomized dogs resulted in a marked increase in the levels of plasma 17-hydroxypregnenolone and dehydroepiandrosterone. However, our data show an ACTH-induced rise in 5-androstene-3 beta. 17 beta-diol in intact and castrated dogs, thus suggesting that this steroid is a good parameter to assess in the stimulation of adrenal steroidogenesis by ACTH.     

Intranasal administration of ACTH(1-24) stimulates catecholamine secretion.

Previously, we reported that intranasal (IN) ACTH(1-24) administration stimulates adrenocortical steroid secretion in normal subjects. To determine the efficiency of transmucosal absorption of ACTH into the adrenal medulla, we measured serum cortisol, aldosterone, epinephrine, norepinephrine and dopamine levels after IN vs. intravenous (IV) administration of 250 microg ACTH(1-24) in 7 healthy adult men (mean age 21.7 +/- 1.2 yr; range, 21 - 24 yr). Blood was collected at 0, 30, 60 and 120 min after administration of ACTH(1-24), and the levels of adrenocortical steroids and catecholamines were measured by specific RIA and HPLC methods, respectively. There were no side effects associated with IN or IV ACTH administration. Consistent with the previous study, serum cortisol and aldosterone increased after IN administration of ACTH(1-24), peaking 30 min after administration. Sixty minutes after IN and IV administration of ACTH, epinephrine levels increased by 41.9 +/- 13.1 % and 63.3 +/- 11.8 %, respectively, and remained elevated throughout the sampling period. Thirty minutes after IN or IV administration of ACTH(1-24), plasma norepinephrine levels increased by 55.9 +/- 13.4 % and 73.7 +/- 15.0 %, respectively, peaking 30 min after ACTH(1-24) administration, and decreasing to basal levels within 60 min. Plasma dopamine levels did not change after IN administration of ACTH(1-24). Adrenocortical steroid and catecholamine levels did not increase after IN administration of saline. These results demonstrate that IN administration of ACTH(1-24) not only stimulates adrenocortical steroids, but also epinephrine and norepinephrine.     

Cortisol and testosterone: Inhibitory agents of the mineralocorticoid pathway. Is there a physiopathological meaning in adrenal tumors?

The authors incubated adrenal mitochondria to study the in vitro action of cortisol and testosterone on the transformation of corticosterone and 18-hydroxycorticosterone into aldosterone. The results show that cortisol at concentrations of 5 × 10⁻⁶ and 10⁻⁴ M inhibit the conversion of corticosterone into aldosterone by 23.6 to 90%; testosterone 5 × 10⁻⁵ and 10⁻⁴ M inhibit the reaction by 78.4 and 87.2%, respectively. The inhibition of the conversion of 18-hydroxycorticosterone into aldosterone is 12.5 to 91% by cortisol with concentrations ranging from 5 × 10⁻⁷ to 5 × 10⁻⁵ M and testosterone 5 × 10⁻⁵ and 10⁻⁴ M inhibits the reaction by 87.3 and 91%, respectively. Aldosterone (10⁻⁸ and 10⁻⁶ M) does not inhibit aldosterone biosynthesis from corticosterone or 18-hydroxycorticosterone. It thus appears that cortisol and testosterone have an effect on the aldosterone biosynthesis pathways in mitochondria. This action may be located at the binding site of the cytochrome P450 11β, which catalyzes all hydroxylation steps in the mineralocorticoid biosynthesis pathway. Because cortisol and testosterone may interfere with aldosterone biosynthesis, and since functional zonation is expected in adrenal carcinomas, the presence of these steroids in substantial amounts could explain the very low plasma aldosterone level usually observed, in adrenal carcinomas studies in our laboratory.     

Assessment of adrenal function by measurement of salivary steroids in response to corticotrophin in patients infected with human immunodeficiency virus

OBJECTIVE: Adrenal insufficiency has been reported among critically ill HIV-infected patients. This is the first study that attempts to detect subclinical hypoadrenal states in non-critical HIV patients through salivary steroids in response to intramuscular low-dose ACTH injection. PATIENTS AND METHODS: We studied 21 ambulatory adult HIV-infected patients without specific clinical signs or symptoms of adrenal insufficiency. Normal salivary flow-rate and salivary alpha-amylase activity confirmed adequate salivary gland function. Salivary cortisol (SAF) and salivary aldosterone (SAL) were obtained at baseline and 30 min after the injection of 25 microg of ACTH in the deltoid muscle (LDT(s)). Assessment of salivary steroids after stimulation with 250 microg of intramuscular ACTH (HDT(s)) was performed on those who hyporesponded to LDT(s). Basal blood samples were drawn for steroids, renin and ACTH measurements. RESULTS: At baseline SAF and SAL correlated significantly (p=0.0001) with basal serum cortisol and aldosterone (r=0.70 and 0.91, respectively). Plasma ACTH and renin concentrations were within the normal range in all patients. Eight of the twenty-one HIV(+) patients were LDT(s) hyporesponders in either SAF (n:1) or SAL (n:7). LDT(s) repeated in six cases after a year reconfirmed the impairment of aldosterone secretion. LDT(s) hyporesponders had normal steroid responses to HDT(s). CONCLUSIONS: LDT(s) is a simple, safe, well-accepted and non-invasive approach to assess adrenal function in HIV-infected ambulatory patients. It revealed subnormal cortisol (5%) and aldosterone responses (33%) when HDT(s) results were normal.     

Effect of ACTH (tetracosactide) on steroid hormone levels in the mare. Part A: effect in intact normal mares and mares with possible estrous related behavioral abnormalities

Ovariectomized mares and mares with inactive ovaries may show signs of estrus. The reason behind this phenomenon is not clear; however, steroid hormones of adrenal origin have been suggested. Moreover, aberrant adrenal hormone production has been implied as a reason why some intact mares may change behavior. In the present study, the effect of ACTH on plasma levels of cortisol, progesterone, androstenedione and testosterone was investigated in intact mares with normal estrous behavior ('controls', n=5) and intact mares that according to their owners showed deviant estrous behavior ('problem' mares, n=7). Blood samples were collected hourly from 12:00 h until 14:00 h the following day (half-hourly between 14:00 and 17:00 h) on two occasions (at two estruses), with saline or ACTH treatment (tetracosactide) at 14:00 h (saline treatment day or ACTH treatment day). ACTH treatment caused a significant increase in plasma levels of cortisol, progesterone, androstenedione and testosterone in all mares (P<0.05). An overall significant difference in cortisol response to ACTH was found (P<0.05), with 'problem' mares showing a significantly lower increase in cortisol levels 30 min to 3h post ACTH treatment (P<0.001). The 'problem' mares also showed a significantly higher increase than controls in progesterone levels in the same time period (P<0.05). The reason for the reduced adreno-cortical reactivity, with a low cortisol response to the ACTH treatment, in the 'problem' mares is unknown, but may indicate a difference in adrenal function as compared to control mares.     

Effect of angiotensin II on secretion of adrenal androgens

To assess the effect of angiotensin II (A II) on the secretion of human adrenal androgens (AA), plasma dehydroepiandrosterone (DHEA), DHEA sulfate (DS) and delta 4-androstenedione (delta 4-A) were measured in eight normal men 60 and 120 min after stimulation of endogenous A II by a bolus injection of 40 mg frusemide, and the direct effect of A II on the secretion of adrenal androgens was examined in cultured human adrenocortical cells in the presence of a low concentration of ACTH. The administration of frusemide led to a significant increase in the plasma DHEA and DS concentration as well as plasma renin activity (PRA) and aldosterone concentration (PAC), but did not change plasma cortisol and delta 4-A. In the culture of human adrenocortical cells, 10(-9)-10(-5) M A II or 10(-13) M ACTH alone did not stimulate the secretion of DHEA, DS and delta 4-A, while 10(-7) and 10(-5) M A II in the presence of 10(-13) M ACTH caused a significant increase in DHEA and DS secretion with no change in delta 4-A. These results suggest that the activated renin-angiotensin system stimulates the secretion of adrenal androgens by a direct effect of A II on adrenal cortical cells.     

Response of plasma adrenal steroids to synthetic ACTH under ketoconazole in man

We have investigated the effect of a single oral administration of 600 mg ketoconazole, an imidazole derivative used in clinical practice as an antimycotic agent, on the response of plasma adrenocortical steroids to 1-24 ACTH in 5 normal male subjects pretreated with dexamethasone. The 2 mg of dexamethasone was administered orally at 2300 h on the preceding night, and then a rapid ACTH test was started at 0830 h. After a 1 week interval, the ACTH test was repeated in the same manner under the same dexamethasone pretreatment, but 600 mg of ketoconazole was given orally at 0500 h. The absolute plasma concentration and the increase over the basal level of each steroid after ACTH were evaluated and compared in both conditions with and without ketoconazole administration. A single ingestion of ketoconazole caused a decrease in both indices of the responsiveness of plasma dehydroepiandrosterone and a rise in the plasma level of 17 alpha-hydroxypregnenolone. The response of plasma aldosterone was clearly blunted by ketoconazole administration, whereas that of plasma corticosterone was clearly increased. Ketoconazole also blocked the response of plasma cortisol with concomitantly increased responses of plasma 11-deoxycortisol and 11-deoxycorticosterone. The increased response of plasma corticosterone seemed to be likely due to the severe inhibitory action of ketoconazole on the conversion of corticosterone to aldosterone. These results imply the inhibitory effect of ketoconazole on C17-20-lyase activity and on the conversion of corticosterone to aldosterone, and suggest an inhibitory action on 11 beta-hydroxylase activity. The effects of ketoconazole on the other enzyme activities in adrenal steroid biosynthesis were also discussed.     

The effect of DHAS on steroidogenesis of the human corpus luteum.

To examine whether or not dehydroepiandrosterone sulfate (DHAS) is a substrate for steroidogenesis in the corpus luteum, we studied 17 women in the luteal phase, the follicular phase, and after castration. Following suppression of adrenal function with dexamethasone, DHAS was administered intravenously and the serum levels of DHAS, dehydroepiandrosterone (DHA), androstenedione (ADS), testosterone (T), 17 beta-estradiol (E2) and progesterone (P) were measured serially for 24 h. An obvious increase in the serum levels of all steroids except for E2 and P was observed in each subject for at least 8 h after DHAS administration. To evaluate the effect of DHAS on the serum levels of the steroid hormones, the integrated response area (IRA) was calculated for each hormone in all the subjects. The IRA values for ADS, T and E2 (at 2 and 4 h) in the luteal phase group were significantly higher than in the other DHAS treated groups, and the IRA values for DHA and P tended to be higher than in the other groups. These results suggest that the corpus luteum utilizes serum DHAS as a substrate for steroidogenesis.     

ADRENOCORTICAL FUNCTION IN PINNIPED HYPONATREMIA

Potentially fatal sodium imbalance occurs in captive and free-ranging pinnipeds and is associated with a variety of stressors. We sought to determine the role of adrenal hormones, principally aldosterone, in the development of this condition. To induce hyponatremia, two ringed seals, Phoca hispida , were maintained in fresh water and fed a low-sodium diet; as controls, two other ringed seals were held in salt water and received a salt-supplemented diet. After 3–6 mo, adrenocorticotropic hormone (ACTH) was used to assess adrenocortical function. In normonatremic control seals, ACTH produced a 2-j-fold increase in circulating cortisol and a 7-fold increase in aldosterone. One of the experimental seals maintained normal plasma sodium levels, and ACTH elicited an exaggerated aldosterone response. The other salt-deprived seal became hypo-natremic, and ACTH had little effect on plasma aldosterone levels. An ACTH stimulation test performed on a spontaneously hyponatremic harp seal, P. groenlandica , which had been maintained in a salt-rich environment, failed to elicit cortisol or aldosterone secretion from the adrenal cortex. This study demonstrated the unusual sensitivity of the seal's zona glomerulosa to central stimulation, providing a mechanism through which the stress response might exhaust adrenal hormone reserves or desensitize the cortex to other physiological stimuli.     

Hormones and behavior of prepubertal and peripubertal chimpanzees

Twenty-one chimpanzees ranging in age from 2.9 to 9.2 years at the midpoint of a study consisting of five 4-week blocks were studied behaviorally in four groups of five or six animals per group, balanced for age and sex. Blood samples for radioimmunoassay of follicle-stimulating hormone (FSH), luteinizing hormone, 17 beta-estradiol, testosterone, dehydroepiandrosterone (DHA), DHA sulfate (DHAS), and cortisol were obtained once each 4-week block. Sex differences were found only in the categories of play duration and initiative and genital inspection, all of which were greater for the males. Several categories (6) of play and other affiliative behaviors were negatively correlated with age and/or body weight for the males, whereas fewer of those categories (2) were so correlated in the females. Hierarchical behavior, genital inspection, solitary behavior other than play, and autogrooming were all positively correlated with age and/or body weight for the males, and only autogrooming for the females. FSH and testosterone levels and testicular volume were positively correlated with age and body weight in the males, whereas for the females cortisol was negatively correlated with body weight and only FSH and the ratios of DHA and DHAS to cortisol were positively correlated with age and/or body weight. Most of the behaviors that were significantly correlated with age and body weight for the males were also correlated in the same direction with FSH and testosterone levels and testicular volume, but not with DHA or DHAS levels. The data are consistent with the view that testosterone, but not the adrenal androgens DHA and DHAS, contributed to the behavioral development of the males. There were few significant correlations between hormones and behavior for the females and interpretation is not clear. The absence of age-related increases in DHA and DHAS of both the males and females, in contrast to the pattern of FSH (and testosterone for the males), supports the growing consensus that adrenarche and puberty are independent developmental processes. The absence of any strong correlations between behavior and levels of the adrenal androgens in either the males or females suggests that adrenarche per se is not a significant event in the behavioral development of chimpanzees.     

Paracrine effects of PAMP and adrenomedullin on the human adrenal H295R cell line: PAMP but not adrenomedullin stimulates DHEA secretion

It has previously been shown, by this laboratory and others, that adrenal cells actively secrete adrenomedullin. Here it is demonstrated that human adrenal cells also secrete the related peptide, proadrenomedullin N-terminal 20 peptide (PAMP). The actions of adrenomedullin and PAMP on adrenal steroid secretion were determined by measuring the aldosterone, cortisol and dehydroepiandrosterone (DHEA) content of cell culture medium after exposure of the human adrenal H295R cells to either PAMP or adrenomedullin. While PAMP was found to cause a dose-dependent increase in release of all the steroids into the medium, adrenomedullin only increased aldosterone and cortisol and had no effect on DHEA. These data suggest that both adrenomedullin and PAMP may be autocrine regulators of adrenal steroid secretion.     

Relationship between functional activity of the adrenal glands and gonads in monkeys during puberty]

Testicular and adrenal cortex endocrine functions were simultaneously tested in pubertal baboons (papio hamadryas) during one year. Concentrations of androgens (testosterone, 5 alpha-dihydrotestosterone, dehydroepiandrosterone), corticosteroids (cortisol, progesterone, 17-hydroxyprogesterone, 17-hydroxypregnenolone) and aldosterone were determined in blood of the experimental monkeys by radioimmunoassay. It was shown that with increasing androgen (testosterone and dihydrotestosterone) levels in blood of the pubertal monkeys there was a significant decrease of corticosteroid concentration which was most pronounced in the monkeys with maximum increase of testosterone level. Described hormonal changes did not influence aldosterone concentration.     

Differences in cortisol, aldosterone and testosterone responses to ACTH 1-17 administered at two different times of day

The effects of 100 micrograms, i.m. of the analog ACTH 1-17 administered at 0800 and 1800 on the secretion of cortisol, aldosterone and testosterone have been studied in normal subjects: 8 male and 8 female. The group as a whole and the males had significantly greater absolute and percent increments in plasma cortisol after administration at 1800. In the females, there was only a greater percent increment in cortisol after the evening administration. The heptadecapeptide always significantly stimulated serum aldosterone, with no difference between the two times of administration. In the females, ACTH 1-17 significantly stimulated testosterone, with a more protracted secretion after the evening administration. In the males, there was always a significant testosterone decrease after the administration of the drug, with no difference between morning and evening. In conclusion, 100 micrograms i.m. of the analog ACTH 1-17 stimulates cortisol secretion more when given during the circadian nadir of plasma cortisol, but only in men. ACTH 1-17 increases testosterone in women and decreases it in men, whereas it seems to increase aldosterone secretion in both sexes.     

Suppression of basal plasma cortisol and adrenal androgen concentrations, but not of ACTH and cortisol responses to hCRH by low-dose dexamethasone in rhesus monkeys

Glucocorticoid treatment at replacement doses does not result in a suppression of ACTH and cortisol responses to corticotropin-releasing hormone (CRH), while basal plasma concentrations of cortisol and adrenal androgens are efficiently suppressed 34 h after starting treatment. This finding could be demonstrated in rhesus monkeys receiving a continuous infusion of dexamethasone (1 microgram/kg per h) for 48 h and confirms our observations in patients on alternate-day prednisone therapy and in patients with congenital adrenal hyperplasia on glucocorticoid replacement therapy. We conclude that the decrease of basal adrenal steroid secretion resulting from glucocorticoid replacement therapy represents an effect on hypothalamic rather than on pituitary function.