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.     

Effect of ACTH and prolactin on dehydroepiandrosterone, its sulfate ester and cortisol production by normal and tumorous human adrenocortical cells

The effect of ACTH and prolactin on the synthesis of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) was studied in cell suspensions of "normal" and tumorous (adenoma) human adrenal cortex. A stimulation of DHEA and no response of DHEAS production by ACTH in "normal" adrenocortical cell suspension was observed. However ACTH stimulated both DHEA and DHEAS synthesis in tumorous adrenocortical cells. Prolactin did not influence either the basal or the ACTH stimulated DHEA and DHEAS production of adrenocortical cells irrespective of their origin. Our results are compatible with the concept that the biosynthesis of DHEA is under ACTH control, while other factor(s) regulate(s) the sulfate pathway of DHEA secretion under normal conditions. In tumorous adrenocortical cells DHEA may be regulated--at least partly--by ACTH. Prolactin seems to have no direct effect on DHEA and DHEAS synthesis. It is postulated that the relationship between serum prolactin and DHEAS (or DHEA) levels observed by several authors might be an extraadrenal effect of prolactin on adrenal androgens.     

Do DHEA/DHEAS play a protective role in coronary heart disease?

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS), the major androgens secreted by human adrenal glands, were suggested to play a protective role in the pathogenesis of atherosclerosis and coronary heart disease. On the basis of a critical review of all existing studies we concluded that 1) there is no evidence of a protective role of DHEA and DHEAS in women, and 2) men with low plasma DHEA and DHEAS levels can be considered as beings at risk of developing a fatal cardiovascular event. These androgens can interfere with atherogenic process by several mechanisms. They influence enzymes such as glucoso-6-phosphate dehydrogenase, which can modify the lipid spectrum. Furthermore, they can inhibit human platelet aggregation, enhance fibrinolysis, slow down cell proliferation and reduce plasma levels of plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen. We suggest that all these DHEA(S) actions are dependent on sex hormone metabolic pathways. There are still insufficient data to advise DHEA supplementation in elderly men, but this type of hormone replacement therapy merits further studies.     

Effects of gemfibrozil treatment on serum levels of androstanediol glucuronide and adrenal androgens.

We have prospectively investigated the role of adrenal cortical androgens as a risk factor for coronary heart disease in the Helsinki Heart Study population. Simultaneously we studied the effects of gemfibrozil treatment on the serum levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and their metabolite androstanediol glucuronide (3 alpha AdiolG) with those of placebo. Gemfibrozil (n = 133) vs placebo (n = 159) treatment was associated with significant elevation of mean (SD) DHEAS (mumol/l) 8.35 (5.31) vs 6.98 (3.85); P less than 0.02, and of 3 alpha AdiolG (nmol/l) 17.45 (7.57) vs 8.62 (3.56); P less than 0.001), and of almost significant elevation of DHEA (nmol/l) 10.12 (6.64) vs 8.78 (5.86); P less than 0.07). These new observations suggest that gemfibrozil treatment increases the production and turnover of DHEA and DHEAS and may in addition stimulate the 5 alpha-reduction of androgens.     

The tempo of human childhood: a maternal foot on the accelerator,a paternal foot on the brake

Relative to the life history of other great apes, that of humans is characterized by early weaning and short interbirth intervals (IBIs). We propose that in modern humans, birth until adrenarche, or the rise in adrenal androgens, developmentally corresponds to the period from birth until weaning in great apes and ancestral hominins. According to this hypothesis, humans achieved short IBIs by subdividing ancestral infancy into a nurseling phase, during which offspring fed at the breast, and a weanling phase, during which offspring fed specially prepared foods. Imprinted genes influence the timing of human weaning and adrenarche, with paternally expressed genes promoting delays in childhood maturation and maternally expressed genes promoting accelerated maturation. These observations suggest that the tempo of human development has been shaped by consequences for the fitness of kin, with faster development increasing maternal fitness at a cost to child fitness. The effects of imprinted genes suggest that the duration of the juvenile period (adrenarche until puberty) has also been shaped by evolutionary conflicts within the family.     

Characterization of serum dehydroepiandrosterone secretion in golden hamsters

Dehydroepiandrosterone (DHEA) is an adrenal androgen whose function is poorly understood. Although DHEA and DHEA sulfate (DHEAS) are secreted in relatively high quantities by the human adrenal, the laboratory rat secretes very little, thus hindering experimental studies of the hormone. In this paper, we measured the changes in serum DHEA and DHEAS under various physiological conditions in golden hamsters. Evening serum DHEAS fell from 6.30 +/- 0.78 microg/dl (mean +/- SE) before surgery to 3.03 +/- 0.23 microg/dl 12 days after bilateral adrenalectomy. Hamsters had higher levels of DHEA and DHEAS in the evening than in the morning, but removal of the gonads did not consistently decrease serum DHEA or DHEAS in males or females. Evening levels of DHEA and DHEAS reached a peak around 7 weeks of age and then gradually decreased to about one-third of these levels by one year of age. These results suggest that DHEA and DHEAS are secreted at least in part from the hamster adrenal, that they do not originate from the gonads, and that there is a daily rhythm with peak levels at a time of day just preceding the active phase. In addition, the levels of these hormones decrease with aging.     

Pharmacokinetics of oral dehydroepiandrosterone (DHEA) in the ovariectomised cynomolgus monkey

Humans and primates are unique in having adrenals that secrete large amounts of DHEA and DHEA-S in the circulation. These steroids act as precursors of active androgens and estrogen's in a long series of peripheral target intracrine tissues. The marked decline of serum DHEA and DHEA-S concentrations with age in men and women has been incriminated in the development of various pathologies. This study provides detailed information on the effect of a single 50mg oral dose of DHEA on circulating estrogen's as well as androgens and their metabolites over 10h in adult ovariectomised (OVX) Cynomolgus monkeys. Serum DHEA, DHEA-S, testosterone (Testo) and androstenedione (4-dione) concentrations increased rapidly with a maximal value at approximately 1h after DHEA administration followed by a 60-80% decrease during the next 2-6h. An important sulfatation of DHEA occurs through first hepatic pass, thus, leading to a marked increase in serum DHEA-S. Serum androst-5-ene-3beta,17beta-diol and androsterone glucuronide (ADT-G) levels remained elevated on a plateau for 6h. Androstan-3alpha,17beta-diol-glucuronide, estradiol and estrone levels remained unchanged. The present data indicate the predominant transformation of the adrenal precursor DHEA into active androgens in peripheral tissues and support the importance of measurement of circulating glucuronide derivatives as index of peripheral or intracrine androgen formation and action.     

Adrenal androgen concentrations increase during infancy in male rhesus macaques (Macaca mulatta)

This study investigated adrenal androgens (AA), gonadotropins, and cortisol in castrated and gonad-intact male rhesus macaques from birth through infancy. Blood samples were collected longitudinally from castrated (n = 6; weekly, 1-40 wk) and intact (n = 4; every other week, 1-17 wk) males. Plasma concentrations of AA were determined by liquid chromatography-tandem mass spectrometry, and plasma concentrations of cortisol and gonadotropins were determined by RIA. Dehydroepiandrosterone sulfate (DHEAS) concentrations increased almost threefold (to 8 wk), dehydroepiandrosterone (DHEA) increased more than eightfold (to 11 wk), and androstenedione doubled (to 15 wk) in five castrated infant males and declined continuously thereafter. A sixth castrated male had markedly different temporal patterns and concentrations (many times more than 2 SDs from the cohort mean) of AA and gonadotropins from first sampling (3 wk) and was excluded from analysis. Cortisol increased over 16 wk but correlated poorly with DHEAS. Luteinizing and follicle-stimulating hormones increased to peaks at 3 and 7 wk, respectively. Testis-intact males exhibited similar profiles, but with earlier peaks of DHEAS (5 wk) and DHEA and androstenedione (7 wk). Peak concentrations of DHEAS were lower and those of DHEA and androstenedione were higher in intact than castrated infants. Testosterone was undetectable in castrated males and >0.5 ng/ml in intact males but was not correlated with DHEA or DHEAS. These are the first data documenting a transient increase in AA secretion during infancy in an Old World primate and are consistent with the previously documented time course of zona reticularis development that accompanies increases in androgen synthetic capacity of the adrenal. The rhesus is a promising model for androgen secretion from the human adrenal cortex.     

Neurosteroid dehydroepiandrosterone and brain function

In the past 30 years it has become clear that the brain tissue and the nervous system are steroidproducing structures. Steroids synthesized in the brain structures are called neurosteroids. This paper summarizes the results of studies on the biosynthesis and metabolism of dehydroepiandrosterone (DHEA), including its metabolism in the adipose tissue, where it serves as a substrate for intracellular formation of biologically active metabolites estradiol and testosterone. The role of sulfatase and sulfotransferase in mutual conversions of DHEA and DHEA sulfate (DHEAS) is described. Species-related differences in the synthesis of DHEA in the adrenal cortex are considered. The adrenal glands of primates (humans and monkeys, including the lower ones) produce large quantities of free and sulfated DHEA. Their synthesis proceeds by the Δ5 pathway: cholesterol → pregnenolone → 17-hydroxypregnenolone → DHEA. The adrenal glands of other species, including rats and mice, do not synthesize DHEA. Out point of view on the possible mechanisms of penetration of endogenous or exogenous DHEA sulfate into the brain structures is described: desulfurization of molecules to form free DHEA penetrating the blood-brain barrier and the possibility of penetration of the sulfate form into the hypothalamic structures, which are not protected by the blood-brain barrier. The results of studies of the use of DHEA as a neurosteroid in clinical practice and the analysis of its role in the development of Alzheimer’s disease, cognitive disorders, and other CNS disorders are also presented. The possible mechanisms underlying the effects of DHEA on the brain are considered. The main neurobiological effects of both forms, DHEA and DHEAS, on the brain structures, which were identified experimentally in various animal models, include the neuroprotective effects, neurogenesis and survival of neurons, apoptosis, and the effect on the synthesis and secretion of catecholamines. Neurosteroids also carry out antioxidative, antiinflammatory, and antiglucocorticoid activity.     

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.     

Measurement of serum levels of dehydroepiandrosterone sulfate: a comparison of radioimmunoassay and enzymatic analysis

Dehydroepiandrosterone sulfate (DHEAS) and unconjugated dehydroepiandrosterone (DHEA) are secretory products of the adrenal cortex. Measurement of serum levels of these steroids is of increasing epidemiologic interest, since low serum concentrations of DHEAS or DHEA have been associated with an increased risk of dying of cardiovascular disease or of developing cancer. Radioimmunoassays (RIAs) are the most convenient systems for the measurement of serum DHEAS concentrations in multiple samples. However, using sera from four individuals we show that different RIA kits provide quite different estimates of serum DHEAS concentrations. Moreover, these results do not always agree with the serum concentrations determined by an independent chromatographic and enzymatic reference method. The results highlight the need for an independent method of determining DHEAS levels in sera that can provide guidance in selecting an appropriate RIA, and in interpreting the results.     

Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans

Dioscorea is a yam steroid extract used in commercial steroid synthesis and consumed by people. DHEA is a steroid which declines with age, but without known activity. This study was designed to determine whether dioscorea supplementation could increase serum dehydroepiandrosterone sulfate (DHEAS) in humans and modulate lipid levels in older people. The subjects were selected volunteers aged 65–82 years. The serum DHEAS level, lipid peroxidation and lipid profile were assessed. Three weeks of dioscorea supplementation had no affect on serum DHEAS level. However DHEA intake of 85 mg/day increased serum DHEA levels 100.3 %. DHEA and dioscorea significantly reduced serum lipid peroxidation, lowered serum triglycerides, phospholipid and increased HDL levels. Both DHEA and the steroid yam extract, dioscorea, have significant activities as antioxidant to modify serum lipid levels.     

Gonadal steroids modulate adrenal fasciculata 3 beta-hydroxysteroid dehydrogenase-isomerase activity in mice.

The observation that adrenal 3 beta-hydroxysteroid dehydrogenase-delta 5----delta 4-isomerase (3 beta HSD) activity is greater in females than in males of both C57BL/6J and C3H/HeJ inbred strains of mice led us to test the hypothesis that this enzyme's activity within the adrenal gland may be modulated by gonadal steroids. Two weeks after sham-operation or castration, no castration effect was seen in adrenal 3 beta HSD activity, but the sex difference had been eliminated in C57BL/6J animals. Gonadal steroids were replaced in castrated animals of both sexes of C57BL/6J and C3H/HeJ mice. Daily injections of androgenic steroids (testosterone propionate or dihydrotestosterone) decreased adrenal 3 beta HSD activity in both sexes of both strains of mouse. Although estradiol benzoate did not alter adrenal 3 beta HSD activity in either sex or strain tested when the activity was expressed on a per adrenal gland basis, it did inhibit adrenal 3 beta HSD activity when expressed on a per milligram of adrenal tissue basis in C57BL/6J but not in C3H/HeJ animals. Histochemical staining for 3 beta HSD and the relationship between adrenal weight and the cross-sectional area of the zona fasciculata suggested that the adrenal zona fasciculata was the target of the inhibitory effects of androgens on adrenal 3 beta HSD activity.     

Androgens in rheumatoid arthritis: when are they effectors?

Neither hormone receptor genes nor plasma androgens seem significantly altered in female subjects before they became affected by rheumatoid arthritis (RA) and, therefore, do not seem to play a role as risk factors for its development. However, serum testosterone levels are inversely correlated with RA activity and dehydro-epiandrosterone sulfate (DHEAS) plasma levels are inversely correlated with both disease duration and clinical severity in patients already affected by active RA. In particular, gonadal and adrenal androgens (that is, testosterone and DHEAS) are significantly decreased in inflamed synovial tissue/fluids during active disease as a consequence of the inflammatory reaction, which supports a pro-inflammatory milieu in RA joints. Recently, male gender has been found to be a major predictor of remission in early RA.     

Gemfibrozil treatment is associated with elevated adrenal androgen, androstanediol glucuronide and cortisol levels in dyslipidemic men

We have investigated the role of steroid hormones as coronary risk factors in Helsinki Heart Study population of dyslipidemic middle-aged men. We compare here the effects of gemfibrozil and placebo on the serum levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), their metabolite androstanediol glucuronide (3-AdiolG), androstenedione, cortisol, testosterone, and sex-hormone binding globulin (SHBG) in non-smokers. We also examined the associations between steroid and lipoprotein levels in both treatment groups. Compared with placebo gemfibrozil treatment was associated with significant elevations of the mean levels of DHEA 10.2 vs 8.0 nmol/1; P<0.005, of DHEAS 8.0 vs 5.8 μmol/1; P<0.001, of 3AdiolG 18.3 vs 8.4 nmol/1; P<0.001, of androstenedione 5.7 vs 5.1 nmol/1; P<0.02, and of cortisol 426 vs 358 nmol/1; P<0.001. The mean SHBG levels decreased from 46.4 to 41.7 nmol/1; P=0.03 with gemfibrozil treatment. No difference was found in testosterone levels 17.7 vs 18.8 nmol/1; P=0.11, or the ratio of testosterone/SHBG 0.45 vs 0.43; P=0.23. Positive correlations were found between high density lipoprotein-cholesterol and DHEAS (r=0.267; P<0.01) and DHEA (r=0.282; P<0.01) levels and negative correlations between low density lipoprotein-cholesterol and 3-AdiolG (r=−0.400; P<0.001) and cortisol (r=−0.281; P<0.01) levels in the gemfibozil group. Our results indicate that gemfibrozil treatment increases the production and turnover of adrenal androgens and cortisol, and suggest that activation of the adrenocorticol function and increased metabolism of androgens are related to the improved lipoprotein pattern during gemfibrozil treatment.     

Adrenarche: postnatal adrenal zonation and hormonal and metabolic regulation

Adrenarche is the direct consequence of the organogenesis of the zona reticularis (ZR). Proliferation of cortical cells could take place in the outermost layers of the adrenal cortex. Cells could then migrate to differentiate the zona glomerulosa (ZG) and zona fasciculata (ZF) during fetal life, and the ZR during postnatal life. After adrenarche, there are detectable increases in circulating DHEA and DHEA-S. Adrenarche could result from an increase in 17,20-lyase activity of P450c17 secondary to high levels of cytochrome b(5) expression, and from a decrease in 3betaHSD2 expression along with an increase in the expression of SULT2A1 in the ZR. The GH-IGF system and insulin, among other factors, might also modulate adrenal androgen production. Furthermore, high concentrations of estradiol enhance basal and ACTH-stimulated DHEA-S production, while aromatase expression was observed in the human adrenal medulla but not in the ZR, suggesting that estrogens produced in the adrenal medulla might be involved in the regulation of androgen production in the ZR. Premature adrenarche might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome in females, as well as with insulin resistance in both sexes. However, many questions remain, transforming adrenal androgens into markers of diseases important for human health.     

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.