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.     

Human adrenal cells that express both 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) contribute to adrenal androstenedione production

Androstenedione is one of several weak androgens produced in the human adrenal gland. 3β-Hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) are both required for androstenedione production. However, previous studies demonstrated the expression of HSD3B2 within the zona glomerulosa (ZG) and fasciculata (ZF) but low levels in the zona reticularis. In contrast, CYB5A expression increases in the zona reticularis (ZR) in human adrenal glands. Although their colocalization has been reported in gonadal theca and Leydig cells this has not been studied in the human adrenal. Therefore, we immonolocalized HSD3B2 and CYB5A in normal human adrenal glands and first demonstrated their co-expression in the cortical cells located at the border between the ZF and ZR in normal human adrenal. Results of in vitro studies using the human adrenal H295R cells treated with the HSD3B2 inhibitor, trilostane, also demonstrated a markedly decreased androstenedione production. Decreasing CYB5A mRNA using its corresponding siRNA also resulted in significant inhibition of androstenedione production in the H295R cells. These findings together indicate that there are a group of cells co-expressing HSD3B2 and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex, and these hybrid cortical cells may play an important role in androstenedione production in human adrenal gland.     

Chronic stress and high sucrose intake cause distinctive morphometric effects in the adrenal glands of post-weaned rats

We investigated the effects of chronic stress combined with high sucrose intake on the morphology of the adrenal glands in young rats. Male Wistar rats were fed a standard chow diet and allocated into control (C; tap water), chronic restraint stress (St), 30% sucrose diet (S30) and 30% sucrose diet + chronic restraint stress (S30 + St) groups. St consisted of 1 h daily sessions, 5 days/week for 4 weeks. Chronic stress reduced the thickness of the zona glomerulosa (ZG) and zona fasciculata (ZF) in both right and left glands; the thickness of the zona reticularis (ZR) was increased in the right gland. Cell density was greater in the ZF and medulla of both right and left glands, whereas cell density increased in the ZR of only the left gland. The percentage of small cells was lower in the ZG, whereas more large cells were found in the left gland. A similar result was obtained for the ZF, ZR and medulla in both right and left glands. Chronic stress increased the area covered by blood vessels in the ZR of the right gland, but decreased the area in the ZR of the left gland. The area covered by blood vessels was reduced in the medulla of both right and left glands in rats subjected to chronic stress. Infiltration of immune cells was increased by chronic stress in all layers of the cortex of the left gland, but was reduced in the medulla of the right gland. A high sucrose diet reduced the thickness of the medulla in the left gland. Cell proliferation increased in the ZG of the right gland and the weight of the right adrenal gland increased. Reduced cell proliferation in the ZG of the left gland was associated with a reduction in the area covered by blood vessels. In addition, the area covered by blood vessels decreased in the medulla of both glands. Our findings demonstrate that exposure to chronic stress during early life causes morphometric changes in adrenal glands.     

Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging.

Dehydroepiandrosterone (DHEA) is produced in prodigious quantities by the human adrenal, principally as the 3-sulfoconjugate DHEA sulfate (DS) during intrauterine life. The fetal zone and neocortex cells of the fetal adrenal express large amounts of DHEA sulfotransferase and minimal amounts, at least until very near the end of gestation, of 3beta-hydroxysteroid dehydrogenase. This pattern of enzyme expression favors substantial secretion of DHEA/DS with minimal cortisol produced; the DHEA/DS serves as the major precursor for placental estrogen formation in human pregnancy. Aside from adrenocorticotropin, other physiologic regulators of growth and steroidogenesis in the fetal adrenal have been postulated to exist, but have yet to be identified. Whereas intrauterine stressors may activate adrenal cortisol secretion, the fetal adrenal responds to many pregnancy conditions by suppressing DHEA/DS formation. After birth, the human adrenal undergoes reorganization whereby the large, inner fetal zone regresses, and DHEA/DS production is diminished. Just prior to gonadal maturation, the human adrenal undergoes morphologic and functional changes (adrenarche) that give rise to a prominent zona reticularis that is characterized by the presence of DHEA sulfotransferase, the absence of 3beta-hydroxysteroid dehydrogenase, and an enhancement of DHEA/DS production. The adrenal of the adult responds to stress in many instances like that of the fetus: increased cortisol secretion and diminished DHEA/DS secretion. The mechanisms for this divergence in the adrenocortical pathway is unknown. With aging, there is suppression of DHEA/DS secretion, possibly as the consequence of an involution of the zona reticularis, but corticosteroid production continues unabated.     

Receptors for insulin and insulin-like growth factor-I in the human adrenal gland

Human adrenal glands contain high-affinity receptors for insulin and insulin-like growth factor I (IGF-I). Comparative studies with rat, hamster and human adrenal membranes confirmed that IGF-I receptors are most abundant in rat and hamster adrenals, whereas insulin and IGF-I receptors are present in equivalent numbers in human adrenal glands. Covalent crosslinking studies revealed that the human adrenal gland IGF-I receptor binding subunit migrated on dodecyl sulfate polyacrylamide gels with Mr = 135,000, which is identical to the migration of IGF-I receptor binding subunits isolated from other tissues. Autoradiography of frozen human adrenal slices incubated with [125I]insulin showed prominent, displaceable binding of this radioligand to the zona reticularis, zona glomerulosa, vasculature and medulla; in contrast, [125I]IGF-I binding to human adrenal tissue was most prominent in the zona reticularis and negligible in the medullary region.     

Adrenal cortex -- the next biological clock?

It is well known that plasma levels of dehydroepiandrosterone (DHEA), a steroid hormone secreted by zona reticularis (ZR) of the adrenal cortex, reach the maximal values in the third decade of life and then gradually decline with age. Moreover, the DHEA deficiency is probably responsible for several functional disturbances connected with aging. It was also found that ZR reaches its definitive volume at puberty and undergoes selective atrophy during the aging. Thus, the decline of DHEA may be a simple consequence of ZR atrophy in aged subjects. A hypothesis presented here attempts to explain the mechanism of the age-related ZR atrophy and is based on the adrenal cortex cell kinetics. In the adrenal cortex the cell proliferation indices are lower when we pass from zona glomerulosa (ZG) to the inner zones and are the lowest in ZR. In contrast, the apoptotic index is the highest in ZR. It is suggested that adrenocortical cells renew from the progenitor cells located in ZG /zona fasculata boundary and /or in subcapsular layer. These cells migrate centripetally undergoing the subsequent steps of differention and consecutive divisions - and - if not die en route - reach the most central localization in ZR. In consequence, ZR includes the "oldest" adrenocortical cells which probably in majority reached the "Hayflick's number" and cannot divide. This results in the preponderance of apoptosis over proliferation leading to progressive ZR atrophy followed by a decline of secretion of ZR-derived steroid hormones.     

Ovine prolactin potentiates the action of adrenocorticotropic hormone on the secretion of dehydroepiandrosterone sulfate and dehydroepiandrosterone from cultured bovine adrenal cells

To determine the direct effect of prolactin on adrenal androgen secretion, the daily secretions of dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione and cortisol were determined in monolayer culture of bovine adrenal cells in the presence or absence of adrenocorticotropic hormone (ACTH) and/or prolactin. In the absence of ACTH ovine prolactin alone had no effect on steroid secretion during seven-day culture. Ovine prolactin, when administered in combination with ACTH, significantly potentiated the stimulatory effect of ACTH on DHEA-S and DHEA but not androstenedione secretion on the seventh day in culture. On the first day in culture prolactin showed no synergistic effect with ACTH on DHEA and DHEA-S secretion, although ACTH significantly increased DHEA and cortisol secretion. DHEA-S secretion increased as a function of prolactin concentration in the presence of ACTH. These results indicated that long-term treatment by ovine prolactin with ACTH caused the increase in adrenal androgen secretion from bovine adrenal cells. The site of action of prolactin was suggested to be the partial inhibition of adrenal 3 beta-hydroxysteroid dehydrogenase by the result of increases in DHEA-S and DHEA but not androstenedione secretion.     

Sex differences in adrenocortical structure and function

Summary Adrenal glands of adult male hamsters are larger and secrete more cortisol than those of females. Stereology was therefore used to study zonal and cellular aspects of development of the adrenal cortex of male and female hamsters. Adrenal glands were studied at weekly intervals from day 21 to day 77 of postnatal ontogenesis. Within this period, body weight did not differ significantly between the sexes. During development, absolute and relative adrenal weights were higher in males; their zona glomerulosa (ZG), zona fasciculata (ZF) and zona reticularis (ZR) become markedly larger than those in females. No marked changes in the volume of individual ZG cells occurred although ZF cells and ZR cells become larger in male than female animals. The total number of adrenocortical cells increased within the period studied, a greater increase being observed in ZG and ZF in males. No distinct sex difference was observed in the number of ZR cells throughout development. From day 56 of postnatal life the adrenal cortex of male hamster contained more parenchymal cells than the female gland. These results thus indicate that sex differences in hamster adrenal cortex depend upon changes in number and size of parenchymal cells.Supported in part by a grant from the Committee of Zoology, Polish Academy of Sciences     

Adrenal androgen production in catarrhine primates and the evolution of adrenarche

Adrenarche is a developmental event involving differentiation of the adrenal gland and production of adrenal androgens, and has been hypothesized to play a role in the extension of the preadolescent phase of human ontogeny. It remains unclear whether any nonhuman primate species shows a similar suite of endocrine, biochemical, and morphological changes as are encompassed by human adrenarche. Here, we report serum concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) measured in 698 cross-sectional and mixed longitudinal serum samples from catarrhine primates ranging from 0.6 to 47 years of age. DHEAS in Pan is most similar to that of humans in both age-related pattern and absolute levels, and a transient early increase appears to be present in Gorilla. DHEA levels are highest in Cercocebus, Cercopithecus, and Macaca. We also tested for evidence of adaptive evolution in six genes that code for proteins involved in DHEA/S synthesis. Our genetic analyses demonstrate the protein-coding regions of these genes are highly conserved among sampled primates. We describe a tandem gene duplication event probably mediated by a retrotransposon that resulted in two 3-β-hydroxysteroid dehydrogenase/Delta 5-Delta 4 genes (HSD3B1 and HSD3B2) with tissue specific functions in catarrhines. In humans, HSD3B2 is expressed primarily in the adrenals, ovary, and testis, while HSD3B1 is expressed in the placenta. Taken together, our findings suggest that while adrenarche has been suggested to be unique to hominoids, the evolutionary roots for this developmental stage are more ancient.     

促肾上腺皮质激素引起大鼠肾上腺c-fos原癌基因表达的免疫组化研究

采用冰冻切片及免疫组化法观察了注射促肾上腺皮质激素(ACTH,75U/kg)、胰岛素及正常对照大鼠中肾上腺各部分c-fos原癌基因表达产物Fos蛋白的出现和分布特点。结果表明注射ACTH后90min,大鼠肾上腺皮质网状带出现Fos蛋白染色阳性细胞,阳性染色物集中于细胞核,肾上腺皮质束状带仅见少数Fos蛋白染色阳性细胞,肾上腺髓质则未见Fos蛋白染色阳性细胞。与注射ACTH相反,注射胰岛素引起肾上腺髓质出现Fos蛋白染色阳性细胞。注射生理盐水对照组动物肾上腺皮质和髓质均未见Fos蛋白染色阳性细胞。上述结果表明,注射ACTH或胰岛素可以引起大鼠肾上腺不同部位c-fos原癌基因表达。     

Human-like adrenal development in wild chimpanzees: A longitudinal study of urinary dehydroepiandrosterone-sulfate and cortisol

The development of the adrenal cortex varies considerably across primates, being most conspicuous in humans, where a functional zona reticularis–the site of dehydroepiandrosterone-sulfate (DHEA/S) production–does not develop until middle childhood (5–8 years). Prior reports suggest that a human-like adrenarche, associated with a sharp prepubertal increase in DHEA/S, may only occur in the genus Pan. However, the timing and variability in adrenarche in chimpanzees remain poorly described, owing to the lack of longitudinal data, or data from wild populations. Here, we use urine samples from East African chimpanzees (Pan troglodytes schweinfurthii) collected over 20 years at Kanyawara in Kibale National Park, Uganda, to trace the developmental trajectories of DHEAS (n = 1,385 samples, 53 individuals) and cortisol (n = 12,726 samples, 68 individuals). We used generalized additive models (GAM) to investigate the relationship between age, sex, and hormone levels. Adrenarche began earlier in chimpanzees (~2–3 years) compared with what has been reported in humans (6–8 years) and, unlike humans, male and female chimpanzees did not differ significantly in the timing of adrenarche nor in DHEAS concentrations overall. Similar to what has been reported in humans, cortisol production decreased through early life, reaching a nadir around puberty (8–11 years), and a sex difference emerged with males exhibiting higher urinary cortisol levels compared with females by early adulthood (15–16 years). Our study establishes that wild chimpanzees exhibit a human-like pattern of cortisol production during development and corroborates prior reports from captive chimpanzees of a human-like adrenarche, accompanied by significant developmental increases in DHEAS. While the role of these developmental hormone shifts are as yet unclear, they have been implicated in stages of rapid behavioral development once thought unique to humans, especially in regard to explaining the divergence of female and male social behavior before pubertal increases in gonadal hormones.     

Adrenarche in Prader-Willi syndrome appears not related to insulin sensitivity and serum adiponectin

Prader-Willi syndrome (PWS) is a genetic disorder characterized by dysmorphic features, obesity, hypogonadism, hypotonia and mental retardation. Obesity has been linked to insulin resistance and the latter has also been associated with premature adrenarche. Since up to date a controlled study to investigate adrenarche and its hormonal regulation was lacking in PWS, our aim was to assess whether prepubertal PWS patients develop premature adrenarche and its relationship with markers of insulin sensitivity. Fourteen prepubertal children with PWS (6 M, 8 F) and 10 non-syndromal simple obese matched controls (5 M, 5 F) participated (mean age: 7.62 +/- 1.84 years). A fasting blood sample was obtained for adrenal and ovarian androgens, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1, leptin, adiponectin and a lipid profile. Thereafter an oral glucose tolerance test was performed. PWS patients were smaller at birth and a higher proportion displayed premature pubarche. No differences were found in testosterone, androstenedione, sex hormone binding globulin, free androgen index, homeostatic model assessment-IR, 2-hour insulin, leptin or adiponectin levels. 17-hydroxyprogesterone and DHEAS levels however, were significantly higher in PWS. IGF-I levels were significantly lower in PWS and correlated significantly with height SDS (p < 0.05). In conclusion, a higher proportion of premature adrenarche in our PW patients was observed, which was not explained by differences in insulin sensitivity or plasma levels of adipokines and IGF-I.     

Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study.

Premature adrenarche is a condition characterized by precocious development of pubic and/or axillary hair, due to early onset of adrenal androgen secretion. Girls with premature adrenarche may later develop menstrual irregularities, hyperandrogenism, and the classic polycystic ovary syndrome. As leptin is thought to modulate the onset of pubertal development, we measured plasma leptin levels in 7 girls with premature adrenarche, and 8 age-matched comparison girls. Because leptin, the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-gonadal axes are functionally interrelated, we also determined salivary and plasma cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, estradiol, and estrone. Finally, since IGF-I may play a role in adrenocortical function, we determined plasma levels of IGF-1, and IGF-BP1. Plasma was collected by an intravenous catheter at times 0, 20, and 40 min, starting at 1.30 p.m. Girls with premature adrenarche had a higher body mass index (BMI) and an over two-fold elevation of their plasma leptin than comparison girls. This group also had elevated levels of salivary and plasma cortisol, and increased levels of DHEA, DHEA-S, androstenedione, estradiol and estrone. Plasma IGF-1 and the ratio of IGF-1/IGF-BP1 were elevated. We propose that girls with premature adrenarche may represent an overlapping group characterized by both features of increased adiposity and HPA axis activity, which together, and depending on the genetic/constitutional background of the individual, may account for the development of adrenal hyperandrogenism, and, later, the polycystic ovary syndrome.     

Bromocriptine treatment in anovulation with decreased ratio of follicle stimulating hormone to luteinizing hormone and with hyperandrogenism

Twenty-six anovulatory women of polycystic ovarian (PCO)-type were treated with bromocriptine (Br) at a daily dose of 5 mg for 2 months. Ovulatory cycles were resumed in 18 (69.2%) women (Br-responders). No difference between pretreatment serum levels of FSH, LH, PRL and estradiol and FSH/LH ratios in Br-responders and nonresponders was observed. The geometric mean of circulating androstenedione (A-dione) in Br-responders (2.58 ng/ml) appeared higher than that in nonresponders (2.11 ng/ml) but was not statistically significant. The geometric mean of dehydroepiandtrosterone sulfate (DHEA-S) in Br-responders (1652 ng/ml) was lower (p less than 0.01) than that in nonresponders (2582 ng/ml). The ratio of DHEA-S to A-dione (D/A ratio) exhibited a highly significant between-group difference (p less than 0.001) (646 and 1222 for Br-responders and nonresponders, respectively). Br-nonresponders with high DHEA-S levels and D/A ratios tended to hyperproduction of adrenal androgen, and Br-responders with high A-dione levels and low D/A ratios to hyperproduction of ovarian androgen. The present study indicates that Br is effective in PCO-type women presumably with ovarian androgen hyperproduction. The efficacy of Br, when applied to PCO-type women, could be predicted with their D/A ratios.     

Reduced quality and accelerated follicle loss with female reproductive aging - does decline in theca dehydroepiandrosterone (DHEA) underlie the problem?

Infertility, spontaneous abortion and conception of trisomic offspring increase exponentially with age in mammals but in women there is an apparent acceleration in the rate from about age 37. The problems mostly commonly occur when the ovarian pool of follicles is depleted to a critical level with age but are also found in low follicular reserve of other etiologies. Since recent clinical studies have indicated that dehydroepiandrosterone (DHEA) supplementation may reverse the problem of oocyte quality, this review of the literature was undertaken in an attempt to find an explanation of why this is effective?In affected ovaries, oxygenation of follicular fluid is low, ultrastructural disturbances especially of mitochondria, occur in granulosa cells and oocytes, and considerable disturbances of meiosis occur. There is, however, no evidence to date that primordial follicles are compromised. In females with normal fertility, pre-antral ovarian theca cells respond to stimulation by inhibin B to provide androgen-based support for the developing follicle. With depletion of follicle numbers, inhibin B is reduced with consequent reduction in theca DHEA. Theca cells are the sole ovarian site of synthesis of DHEA, which is both a precursor of androstenedione and an essential ligand for peroxisome proliferator-activated receptor alpha (PPARα), the key promoter of genes affecting fatty acid metabolism and fat transport and genes critical to mitochondrial function. As well as inducing a plethora of deleterious changes in follicular cytoplasmic structure and function, the omega 9 palmitate/oleate ratio is increased by lowered activity of PPARα. This provides conditions for increased ceramide synthesis and follicular loss through ceramide-induced apoptosis is accelerated.In humans critical theca DHEA synthesis occurs at about 70 days prior to ovulation thus effective supplementation needs to be undertaken about four months prior to intended conception; timing which is also suggested by successful interventions to date. In humans and primates that undergo adrenarche, the adrenal zona reticularis (ZR) is the major site of DHEA production, however this is also reduced with age. Concomitant loss in function of the ZR might account for the acceleration in the rate of aging seen in humans in the late thirties’ age group.     

Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency

The effect of human growth hormone (hGH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 5/12 to 14 8/12 years (median 12 years). Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and urinary excretion of 17-ketosteroids (17-KS) and free cortisol were determined before, during short-term (2 U/day X 3) and after long-term (6 months) treatment with hGH. No significant change was noted in the plasma concentration or urinary excretion of steroids during the short-term administration of hGH. Despite a significant increase in growth velocity during 6 months of hGH therapy (8.2 vs. 4.5 cm/year, p less than 0.01), the plasma concentrations of DHEA-S and the urinary 17-KS and free cortisol levels were unchanged. These results fail to substantiate a role for hGH in the physiologic control of adrenal androgen secretion. Thus, the low plasma levels of adrenal androgens sometimes seen in GH-deficient patients are not due to the absence of GH per se.     

Adrenopause

Dehydroepiandrosterone(DHEA) and DHEA-S are steroids that are abundantly produced by the adrenal gland. Plasma concentrations of DHEA and DHEA-S increase during adrenarche but decrease steadily after puberty. Although DHEA and DHEA-S have few intrinsic androgenic actions, they have recently attracted widespread attention due to their beneficial anti-aging effects. We clarified the beneficial effects of DHEA as an anti-aging steroid with regard to its stimulation of the immune system and its anti-diabetes, anti-atherosclerosis, anti-dementia (neurosteroid), anti-obesity and anti-osteoporosis effects. There are two possible biochemical and molecular mechanisms: direct action via the DHEA receptor on the target gene; and indirect action. We identified a high affinity of DHEA binding in human T-lymphocytes by searching for the target genes that are induced in activated T-lymphocytes in the presence of DHEA, determined the gene sequence and named DHEA-induced dual p38-specific phosphatase (DDSP). DDSP transgenic mice have been created to identify the anti-aging effects of DDSP. The conversion of DHEA to estrone by cytochrome P450 aromatase in primary cultured human osteoblasts was clarified. We are currently undertaking an open trial of DHEA replacement therapy.     

Identification of aldosterone secretion inhibitory factor in bovine adrenal medulla

We report the first demonstration of an Aldosterone Secretion Inhibitory Factor (ASIF) in acid extracts of bovine adrenal medulla. Following separation from catecholamines and enkephalins, this factor leads to an 80% inhibition of PGE1-stimulated secretion of aldosterone from bovine adrenal zona glomerulosa. ASIF is retained on cation exchange gels and behaves as a small 5K-dalton peptide on Sephadex G-50. This factor cross-reacts in a radio-receptor assay for [125I] atrial natriuretic factor (ANF). ASIF is distinct from all neuropeptides formerly detected in the adrenal medulla, e.g. somatostatin, enkephalin, neuropeptide Y, dynorphin, neurotensin. In the adrenal gland, this ANF-like factor is predominantly found in the medulla (4 pmol/mg protein), with only trace amounts in the cortex (0.1 pmol/mg protein). ASIF might perhaps correspond to the endogenous ligand for the receptor sites that we have previously identified with [125I]ANF in bovine adrenal cortex and could contribute to the formerly reported attenuating influence of the adrenal medulla on mineralocorticoid production.     

Proliferation and distribution of adrenocortical cells in the gland of ACTH- or dexamethasone-treated rats

The effects of prolonged (7-day) ACTH and dexamethasone administrations on rat adrenocortical-cell turnover have been investigated by combined stereological and metaphase-arrest techniques. ACTH was found to increase the number of parenchymal cells in each adrenal zone; however, ACTH altered the cell distribution in the cortex, lowering their percentage in the zona glomerulosa (ZG) and zona fasciculata (ZF) and enhancing it in the zona reticularis (ZR). The cell birth-rate was markedly raised by ACTH exclusively in ZG and ZF. Dexamethasone notably decreased the number of ZF and ZR cells, without altering that of ZG cells. Moreover, dexamethasone increased the percentage of parenchymal cells in ZG and ZF, and lowered it in ZR. In the adrenal cortices of dexamethasone-administered animals, metaphases were virtually absent. These data indicate that ACTH increases the cell birthrate in ZG and possibly ZF, and enhances the centripetal migration of newly-formed cells and their accumulation in ZR. Dexamethasone inhibits both proliferation of adrenocortical cells in the outer cortical layers and their centripetal migration into ZR. Moreover, it appears to cause parenchymal-cell loss in the inner adrenocortical layers.