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Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval) and Laval University, Québec, Canada G1V 4G2
Address all correspondence and requests for reprints to: Pr. Fernand Labrie, Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval), 2705 Laurier Boulevard, Québec, Canada G1V 2G2. E-mail: fernand.labrie{at}crchul.ulaval.ca.
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Abstract |
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After a single 10 mg iv dose of DHEA, the metabolic clearance rate and terminal half-life of DHEA were 99.9 ± 9.1 liter/d and 4.5 ± 0.3 h, respectively. Following a 50-mg DHEA PO dose, systemic availability was only 3.1 ± 0.4%. As shown by their high conversion ratios, the major circulating metabolites of DHEA are DHEA-S, androsterone glucuronide, and androstane-3
,17ß-diol-glucuronide. The conversion ratios of androst-5-ene-3ß,17ß-diol, testosterone, dihydrotestosterone, and androstenedione are, in comparison, small. No transformation to estrogens could be detected in the circulation after either iv or PO DHEA administration.
The present data indicate that DHEA is transformed predominantly into androgens in peripheral tissues in ovariectomized cynomolgus monkeys with minimal (androgens) or no (estrogens) release of the bioactive steroids in the circulation. Furthermore, the present study supports the importance of measuring circulating androgen glucuronide derivatives to assess hormonal exposure of peripheral tissues to androgens after DHEA administration.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsDiscussionReferences |
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-reductase and steroid sulfatase) responsible for the transformation of the adrenal precursors into bioactive sex steroids have been characterized in the human (1). In fact, it is estimated that 100% of estrogens in women after menopause are synthesized in peripheral intracrine tissues from the adrenal C19 steroid precursors and some ovarian testo (1). Furthermore, before menopause, 50% of the serum concentrations of androstenedione (4-dione) and testo derive from peripheral transformation of DHEA-S and DHEA, whereas the other 50% is of ovarian origin (2). It is remarkable that the human has largely vested in sex steroid formation in peripheral tissues while the gonads are the exclusive sources of androgens and estrogens in lower mammals (3). It should also be mentioned that, due to poor diffusion in the extracellular space of the relatively large amount of sex steroids synthesized from DHEA in peripheral intracrine tissues, measurement of the serum levels of bioactive sex steroids underestimates the contribution of the adrenals compared with the gonads by a factor estimated at 10 (4). The secretion of DHEA and DHEA-S by the adrenals increases during adrenarche to reach peak levels between the ages of 20 and 30 yr (5). Thereafter, serum DHEA and DHEA-S decrease progressively to reach 20% of their peak values at the age of 70 yr (5, 6, 7, 8). The marked decline of adrenal C19 steroid secretion with age is therefore associated with profound changes in the body’s hormonal status which have been implicated in the development of various pathologies associated with aging. A series of studies also suggest that supplementation with DHEA in humans and animals could have beneficial effects on many physiologic systems as well as psychological parameters (9, 10, 11, 12, 13, 14, 15, 16, 17, 18). Furthermore, it should be mentioned that the physiological importance of androgens has been neglected in women but is now redeeming clinical interest, especially in the management of menopause (19). Considering the potential effects of DHEA on multiple organ systems by its tissue-selective conversion into androgens and/or estrogens and the possible importance of androgen replacement therapy in post-menopausal women, it is reasonable to suggest that DHEA could be a valid alternative to the present hormone replacement therapy. This is supported by the physiological mechanisms and sites of action of DHEA, which are restricted to the tissues genetically determined to synthesize specific amounts of androgens and/or estrogens through the expression profiles of the various steroidogenic enzymes.
Relatively little information is, however, available on the detailed pharmacokinetics and metabolism of exogenous DHEA in a valid animal model. In the present study, we have used ovariectomized (OVX) dexamethasone (DEX)-suppressed cynomolgus monkeys as model to investigate the effect of various routes of administration of DHEA on circulating androgens, estrogens and their conjugated metabolites.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsDiscussionReferences |
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This study was performed at the animal facilities of the Centre de Recherche du Centre Hospitalier de l’Université Laval (Québec, Canada). Monkeys were selected from the in-house colony of the Molecular Endocrinology and Oncology Research Center. Animals were housed individually or in pairs in standard stainless steel cages in a room maintained at 23 ± 3 C with a 12-h dark, 12-h light cycle (lights on at 0715 h). Animals were fed four primate cookies twice daily at 6 h (±1 h) intervals. Fruits and/or vegetables were distributed twice weekly. Water was available ad libitum. Acclimation to all the procedures was initiated 1 month before the beginning of the study to limit stress and disturbance due to handling and sampling during this experiment (20). Throughout this study, animals were maintained and handled in accordance with the written policies of the Canadian Council on Animal Care and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. This protocol has been approved by the Ethical Committee for Animal Protection of the Centre Hospitalier Universitaire de Québec.
Young adult OVX female cynomolgus monkeys (4 yr old) weighing 3.1–4.0 kg were in good health as verified by a complete veterinary examination, serum biochemistry, and complete blood count. Ovariectomy was performed at least 3 months before the experiments.
Study design
Experiment 1: DEX suppression of adrenal steroids in OVX cynomolgus monkeys (n = 8). Eight females were assigned randomly to two groups of four animals. Group 1 received a 0.5-mg DEX dose im once daily for 7 d between 0800 and 0900 h, whereas animals of group 2 received 1.0 mg of DEX once daily at the same time for 7 d. Blood sampling by venipuncture of the femoral vein without prior sedation was performed immediately after each morning DEX dose.
Experiment 2: assessment of DHEA pharmacokinetic parameters following single iv and oral (PO) dosing of DHEA in DEX-suppressed OVX cynomolgus monkeys (n = 8). Eight females were randomly assigned to two groups of four animals. Adrenal production of steroids was suppressed by once daily administration of 0.5 mg DEX (Azium, Schering-Plough Animal Health) im for 8 d before DHEA administration. Blood samples were drawn from the femoral vein at 0800 h on d 7 to verify basal levels of steroids. On study d 8, group 1 received 10 mg of DHEA (Diosynth, Chicago, IL) in a 87.5% (wt/vol) dimethylsulfoxide (DMSO) solution iv in the saphenous vein, whereas group 2 received a 50 mg DHEA suspension in 12 ml 0.4% (wt/vol) methylycellulose by nasogastric gavage (PO). Blood sampling by venipuncture of the femoral vein without prior sedation was performed at times 0, 4 min, 6 min, 8 min, 15 min, 30 min, 1 h, 4 h, 10 h, and 24 h for the group receiving the iv dose and at times 0, 30 min, 45 min, 1 h, 1 h 15 min, 1 h 30 min, 4 h, 10 h, and 24 h for the group receiving the PO dose. After a 9-d washout period, the monkeys received an identical regimen of DEX. Blood samples were drawn from the femoral vein at 0800 h on d 16 to verify basal levels of steroids. On study d 17, group 1 received the PO dose and group 2 the iv dose. Blood sampling was performed at the same time intervals as indicated above after PO and iv administrations.
Experiment 3: assessment of pharmacokinetic parameters using a continuous iv infusion of DHEA in DEX-suppressed OVX cynomolgus monkeys (n = 4). After a 4-month resting period, four of the female cynomolgus monkeys weighing 3.1–3.2 kg were suppressed with an identical regimen of DEX for 8 d. A catheter was installed under general anesthesia 5 d before DHEA infusion in the right femoral vein. Patency of the catheter was maintained by continuous infusion of Lactate Ringer saline (3 ml/h) and heparin administration once daily. DHEA (2 mg/ml) in an ethanol-polyethylene glycol solution was infused with a Harvard pump (1.2 ml/h) for 12 h. Blood samples were drawn by venipuncture of the left femoral vein without prior sedation once before and during infusion at times 10 h, 10 h 30 min, 11 h, 11 h 30 min, and 12 h as well as after cessation of infusion at 30 min and 1, 2, 4, 10, and 24 h.
Serum steroid measurements
Adrenal and sex steroids and their metabolites were analyzed in the Molecular Endocrinology and Oncology Research Center. Serum concentrations of DHEA, 4-dione, androst-5-ene-3ß,17ß-diol (5-diol), testo, DHT, estrone (E1) and E2 were determined using high performance gas chromatography and negative chemical ionization mass spectrometry. Intra- and interassay precision did not exceed 5.9% for these assays. DHEA-S, androsterone glucuronide (ADT-G), and 3-diol-G serum concentrations were determined using HPLC and mass spectrometry using a PE Sciex API 300 tandem mass spectrometer (Perkin-Elmer, Foster City, CA) equipped with a Turbo ionspray source. Intra- and interassay precision did not exceed 6.4% for these assays. The lower limits of quantification for the assays are presented in Table 1
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Experiment 1: DEX suppression of adrenal steroids in OVX cynomolgus monkeys (n = 8). Data are reported as the mean serum concentration and percent variation of the serum steroid concentration compared with baseline levels ± SEM.
Experiment 2: assessment of DHEA pharmacokinetic parameters following single iv and PO dosing with DHEA in DEX-suppressed OVX cynomolgus monkeys (n = 8).
All data are reported as the means ± SEM. The pharmacokinetic parameters for DHEA were calculated using the noncompartmental analysis from WinNonLin software (version 2.1). The maximum and minimum serum concentrations measured during the study period are reported as Cmax and Cmin, respectively. The time at which Cmax occurred is reported as tmax. Calculation of the areas under the time-concentration curves over 24 h (AUC0
24 h) after PO and iv administrations was performed using the trapezoid rule for all steroids and metabolites and corrected for the basal levels of steroids observed after d 8 of DEX suppression. The systemic availability (F) was calculated from F = (AUC0–24 h PO/AUC0–24 h IV)/ (DIV/DPO), where DIV and DPO are the respective iv and PO doses. The conversion ratios (CR) of precursor to product in the serum (CRPre-Prod) was calculated as the ratios of AUC0–24 h values of the product and precursor after correction of the AUC for the molar mass of each steroid.
Experiment 3: assessment of pharmacokinetic parameters using a continuous iv infusion of DHEA in DEX-suppressed OVX cynomolgus monkeys (n = 4). The metabolic clearance rate (MCR) of DHEA was calculated from the following formula: MCR = (r/DHEA) x (24/1000) where r (ng/h) represents the DHEA infusion rate and DHEA (ng/ml) represents the DHEA serum concentration at equilibrium minus the preinfusion basal DHEA levels. The terminal half-life of the infused DHEA was estimated from the disappearance curve of serum DHEA after termination of the continuous infusion. CR was calculated as the ratio of AUC10–12 h of the product and precursor where AUC10–12 h is the area under the time-concentration curve under steady-state conditions (10 and 12 h) corrected for the basal levels of steroids observed before infusion and the molar mass of each steroid.
Results
Experiment 1: DEX suppression of adrenal steroids in OVX cynomolgus monkeys (n = 8)
DEX administered im once daily for 7 d at the dose of 0.5 or 1.0 mg caused a marked inhibition of the serum concentration of all measured steroids. Serum cortisol rapidly decreased to reach 6.1% and 3.5% of pretreatment levels after 7 d at the 0.5 mg and 1.0 mg daily doses, respectively. Similarly, both doses of the glucocorticoid caused a rapid decrease of serum DHEA and DHEA-S less than 10% of basal levels by d 6, whereas serum 5-diol and 4-dione decreased below the limit of quantification (BLQ) at the same time interval. Serum DHT was BLQ after 2 and 6 d at the 0.5 and 1.0 mg doses, respectively. Compared with their androgenic precursors, ADT-G and 3-diol-G decreased slowly to 20 and 30% of control levels, respectively, after 7 d at both DEX doses (Table 2 and Fig. 1).
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) were calculated at 99.9 ± 9.1 liter/d and 4.5 ± 0.3 h, respectively.
At maximal values, serum concentrations of DHEA-S, 5-diol, and 4-dione increased, on average, by 15,600, 585, and 44.9 nmol/liter above basal DEX-suppressed levels, respectively, whereas testo and DHT, on the other hand, showed much more moderate increases, namely 4.6 and 0.9 nmol/liter over control, respectively (Table 3). The serum concentrations of DHEA-S, 4-dione, and 5-diol increased rapidly with a tmax observed, on average, between 0.1 and 0.3 h, whereas the tmax for testo and DHT occurred later at approximately 0.8 and 4.4 h, respectively (Fig. 2, Table 3). The serum concentrations of DHEA-S, 4-dione, and 5-diol rapidly decreased by about 50% between 0.8 and 2.2 h after DHEA administration. Serum testo, on the other hand, decreased by about 50% at 4 h, whereas serum DHT reached the 50% level much later at 20 h (Fig. 2). Serum E1 and E2 levels did not reach the minimal sensitivity of the assays, namely 30 and 7.3 pmol/liter, respectively (data not shown).
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-diol-G, the two major androgen metabolites measured in the circulation in the monkey and human, reflect the inactivation of the locally synthesized androgens in peripheral tissues. Following the iv dose, serum ADT-G and 3-diol-G increased, on average, by 6316 and 2540 nmol/liter above basal levels (Table 3
). The ADT-G serum concentration increased rapidly to a plateau at 1 h with no tendency to decrease up to 24 h later, whereas the serum 3-diol-G concentration increased much more slowly without reaching a plateau at the last time interval (Fig. 2).
DHEA (50 mg PO)
Following PO administration of 50 mg of DHEA, systemic availability (F) of DHEA measured according to the AUC0–24 h values was only 3.1 ± 0.4% of that measured after iv administration, whereas the t was calculated at 4.3 ± 0.2 h. Mean Cmax values of DHEA, 4-dione and 5-diol were, on average, 453, 86.7, and 46.5 nmol/liter above basal levels, respectively, whereas the Cmax value for DHEA-S was at 41 315 nmol/liter above control. Testo and DHT, on the other hand, showed much more moderate (9.1 and 1.3 nmol/liter) maximal increases (Table 3). The serum concentrations of DHEA, DHEA-S, 4-dione, 5-diol and testo increased rapidly with a maximal value observed, on average, at 0.6–1.6 h (Table 3). Following the early peak values, the serum concentrations of DHEA, DHEA-S and 4-dione decreased rapidly by about 50% 1.3–2.2 h after DHEA administration. Serum testo and 5-diol reached the 50% level at approximately 4 h after the PO dose (Fig. 3). DHT increased more slowly to reach a maximal value at 2.4 h with a progressively slow decrease, thereafter, to reach 50% 24 h after DHEA administration (Fig. 3 and Table 3).
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-diol-G concentration continued to increase progressively up to the 24-h study period to over 7000 nmol/liter above control (Fig. 3 and Table 3). Serum E1 and E2 levels remained below the detection limit after DHEA administration (data not shown).
Comparison of the AUC values provides an estimate of the major serum metabolites associated with the metabolism of DHEA. As indicated by their high conversion ratios, DHEA-S, 3-diol-G, and ADT-G are the major serum metabolites of DHEA after both PO and iv administrations (Table 4). The CR of the weak estrogen 5-diol and of the androgens testo, DHT, and 4-dione are, in comparison, small (Table 5). After PO administration, the CRs for DHEA-S and 4-dione in the first 30 min are similar to those calculated over the 24-h time interval, suggesting a rapid metabolic conversion of DHEA to these steroids, whereas the CRs in the initial 30 min for 5-diol, testo, DHT, and their glucuronidated metabolites indicate slower metabolic pathways for these steroids (Tables 4 and 5).
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-DIOL-G (Fig. 4). Serum DHEA and DHEA-S concentrations stabilized at 1525 and 7020 nmol/liter above DEX-suppressed levels, whereas 5-diol and 4-dione increased by 117 and 23.8 nmol/liter above control, respectively. In comparison, serum testo and DHT stabilized at a mean plateau of 4.1 and 0.7 nmol/liter above basal levels while the glucuronidated metabolite ADT-G reached a plateau of 13 725 nmol/liter above control. On the other hand, serum 3-diol-G increased progressively even after cessation of DHEA infusion (Fig. 4). Continuous infusion of DHEA resulted in a MCRDHEA of 144.6 ± 21.5 liter/d with a terminal half-life after cessation of the infusion measured at 4.5 ± 0.3 h.
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). The CR of the weak estrogen 5-diol and the androgens testo, DHT, and 4-dione are, in comparison, small (Table 5), whereas 3--diol-G continued to increase up to the last time interval studied. |
Discussion |
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In the present study, the OVX young cynomolgus monkey was chosen as model for the postmenopausal women. There are some significant differences in reproductive physiology and DHEA secretion between the human and some other primates. Menopause has only been documented in the rhesus monkey and the baboon at a very late stage of life. The number of appropriate older female available and useful for these studies are, however, very limited (21) Furthermore, DHEA secretion throughout life in the cynomolgus monkey differs from the women notably by an absence of adrenarche (22).
At an adult age, DHEA and 5-reduced C19 steroid glucuronide levels in the female cynomolgus monkey largely exceed the concentrations observed in women. Considering the much lower levels of circulating sulfated steroids in monkeys compared with humans, Guillemette et al. (23) speculated that glucuronidation may be the predominant form of steroid conjugation in the monkey. In fact, based on the AUCproduct/AUCprecursor ratios, we observed that, following PO administration of DHEA, 3-diol-G production is 60-fold greater, whereas DHEA-S production is 4-fold inferior in female cynomolgus than observed in postmenopausal women (24) and DEX-suppressed women (25). Together, these observations would suggest possible downstream differences in the enzymatic conversion of DHEA in the two species.
However, although the ovarian follicles have been shown to produce testo from circulating DHEA-S (26), it is unlikely that ovariectomy would have a significant effect on the metabolism of DHEA in our experimental model. In fact, the large majority of sex steroids are produced locally in peripheral tissues from adrenal precursors in postmenopausal women (27). The steroidogenic enzymes responsible for the transformation of DHEA and DHEA-S into bioactive sex steroids have been characterized in different tissues of the cynomolgus monkey by our laboratory (our unpublished data). The similar expression and the 95% identity between human and monkey enzymes should predict a close, but not necessarily identical (23, 28), metabolism of DHEA in our model. Moreover, we have observed that the calculated MCRDHEA in our OVX and DEX-suppressed cynomolgus monkeys (39.6 ± 7.2 liter/d·kg) is comparable to that observed in women (40 liter/d·kg) and rhesus monkeys (50 liter/d·kg) (29, 30). Such results strongly support the validity of our animal model for metabolic studies of DHEA.
The bioactive sex steroids are either produced by the gonads under the control of pituitary LH or from peripheral conversion of C19 steroid precursors secreted by the adrenals, the secretion of these C19 steroids being under the control of ACTH. Following OVX, the only source of sex steroids remains the adrenals. In women, the ovaries contribute about 50% of circulating testo and 4-dione levels in the early follicular phase (2). Arlt et al. (25) observed an important suppression of serum DHEA (to 21%), DHEA-S (to 13%), 4-dione (to 16%), testo (to 19%), DHT (to 38%), and 3diol-G (to 18%), whereas cortisol was inhibited to 6% of control in young women treated with DEX. The authors concluded that the adrenal contribution to testo and 4-dione is probably higher because both these steroids decreased to less than 30% of baseline. Similarly, we used DEX to induce an almost complete and stable suppression of DHEA, DHEA-S, as well as all derived androgens and conjugated metabolites. Using this model, the pharmacokinetic parameters of DHEA can be determined with minimal interference by endogenous steroids. The almost complete inhibition of adrenal steroids by DEX resulted in a comparable suppression of circulating levels of androgens and their conjugated metabolites, thus indicating the major importance of these adrenal precursors to the total androgen milieu.
Using a limited number of sampling intervals, previous studies on the pharmacokinetics of DHEA in humans were limited to the time course of serum concentrations of DHEA, DHEA-S, and bioactive sex steroids to determine the dose required to restore youthful or normal hormone concentrations and avoid potential deleterious exposure to high steroid levels (14, 24, 25, 31, 32, 33). The present study, using different regimens of DHEA administration, provides clear evidence that serum concentrations of androgenic and estrogenic steroids alone do not reflect adequately the transformation of DHEA into bioactive androgens and estrogens in peripheral target tissues, nor the pool of bioactive sex steroids active in peripheral target tissues. In fact, no increase in circulating estrogens could be measured.
ADT-G and 3-diol-G are the two major metabolites of androgens found in the circulation in both the monkey and human. These steroid derivatives reflect the total androgen pool, namely local androgen biosynthesis in peripheral tissues in addition to the androgens of gonadal origin that enter and act in the same tissues before being inactivated by the same steroid-inactivating enzymes. However, the respective contribution of the liver and peripheral tissues to androgen glucuronides in the circulation remains undetermined (34). As observed in the human, the cynomolgus monkey has high plasma levels of androgen glucuronides in the circulation (23) and uridine diphosphate-glucuronosyltransferase (UGT) 2B enzymes are expressed in various peripheral tissues of the cynomolgus monkey, including the liver (35). At the relatively high doses of DHEA used, both iv and PO administrations of DHEA led to a small increase of the circulating levels of testo and DHT (0.9 to 9.1 nmol/liter) compared with their conjugated metabolites (2,540 to 13,000 nmol/liter). Furthermore, the conversion ratios of testo (0.003–0.03) and DHT (0.002–0.02) were considerably lower than those of ADT-G (16.1–307) and 3-diol-G (1.6–51.9) after both regimens of DHEA administration. Such data clearly show that the circulating levels of the bioactive sex steroids testo and DHT do not reflect accurately the androgenic impact of DHEA. In fact, the 5-reduced C19-steroid glucuronides are likely to better reflect the important transformation of DHEA into androgens in peripheral target tissues. The respective contributions of the liver and other peripheral tissues to the metabolism of DHEA into bioactive sex steroids and their metabolites do, however, remain an important issue to be addressed.
Our study is the first to compare the effect of a PO and a non-PO route of administration on the time course of all major metabolites of DHEA, including the conjugated metabolites of androgens ADT-G and 3-diol-G. One of the major metabolite of DHEA is DHEA-S as shown by its very high CR. Sulfatation of DHEA occurs to a large extent in the liver since sublingual, transdermal, transvaginal, and, in this case, iv administrations of DHEA that all avoid first hepatic pass result in lower DHEA-S to DHEA ratios than those observed after PO administration (36). In fact, sulfotransferase is expressed at a high level in hepatocytes as well as in the adrenals in both the human and monkey (37). Furthermore, the calculated CR for DHEA-S in the initial 30 min is high, thus suggesting that the conversion to DHEA-S begins very early after PO dosing. The parallel decrease of the serum concentrations of DHEA and DHEA-S suggests that the rather long half-life of DHEA observed after PO administration mainly reflects the metabolic back conversion of DHEA-S into DHEA by the action of the ubiquitous sulfatase. DHEA-S thus acts as an important reservoir for DHEA and the resulting bioactive androgens synthesized from DHEA in peripheral target tissues.
The calculated CRs for all free steroids and their glucuronidated metabolites after PO administration were substantially higher than those observed after the iv administration of DHEA. These results also suggest a nonnegligible first hepatic pass effect after PO administration of DHEA. The non-PO route of administration was also shown to dramatically decrease the conversion of DHEA into androgens in women (36). The liver receives 25% of the total blood flow and expresses all the enzymes necessary for the metabolism of DHEA into androgens as well as the UGT enzymes responsible for the specific conjugation of androgens and their 5-reduced metabolites. In fact, five simian UGT2B enzymes have been characterized (UGTB9, 18, 19, 20, and 23) in the liver of the cynomolgus monkey in our laboratory (35).
The CRs for 5-diol, testo, DHT, and their glucuronidated metabolites in the first 30 min were considerably lower than those observed at later times following PO administration. Thus, the greater CRs observed after PO dosing for these steroids is not solely dependent upon the initial first hepatic pass. A rapid kinetic of DHEA may limit the metabolic conversion of DHEA to these metabolites after an acute iv dose. Indeed, over half of the acute iv dose is either distributed to peripheral intracrine tissues or is cleared from the body in the initial 30 min. However, the similar CRs observed for all metabolites after acute and chronic iv regimens suggest that the rapid kinetic is not a limiting factor for the metabolism of DHEA. The metabolism of DHEA to 4-dione, 5-diol, androgens and their glucuronidated metabolites might, in fact, benefit from the greater production of DHEA-S after PO dosing. The sulfated derivative has a longer half-life and may constitute a reservoir of adrenal precursors readily accessible for long time periods to peripheral intracrine tissues. Nevertheless, studies determining more precisely the hepatic extraction and the contribution of other peripheral intracrine tissues should be further evaluated.
A gender-specific difference in the metabolism of exogenous DHEA has been described. DHEA is reported to be preferentially metabolized to estrogens in men and androgens in women (31, 38). Arlt et al. (25) proposed that high gonadal steroids in both men and women could overshadow the respective increases of androgens and estrogens in these two genders. Pharmacologic doses or chronic exposure to DHEA in women caused modest increases of estrogens compared with androgens (25, 33, 39, 40). The present study shows that various regimens of DHEA administration to the female OVX cynomolgus monkey leads predominantly to the formation of androgens and not estrogens. It should be mentioned that the absence of change in circulating estrogens after DHEA administration does not necessarily indicate the absence of estrogenic exposure in specific tissues, which contain the required estrogen-synthesizing enzymes. The circulating levels of the sulfated metabolites of estrogens potentially better reflect the estrogenic metabolism of DHEA in peripheral tissues, although a reliable biomarker of the metabolism of estrogens is yet to be determined (40). Replacement therapies to achieve youthful hormonal levels by DHEA supplementation should take into consideration the fact that steroid concentrations in tissues and not their circulating levels are physiologically meaningful.
A large series of target tissues possess all the enzymatic machinery required to adjust the formation and metabolism of sex steroids to local requirements. Pharmacokinetic studies of DHEA cannot effectively determine the tissue exposure to bioactive sex steroids based upon the circulating levels of these hormones and their metabolites. Measurement of the appropriate serum androgen metabolites such as ADT-G and 3-diol-G is more representative of tissue exposure, but it represents the sum of androgen metabolism in all tissues. It thus appears that the assessment of the tissue specific concentration of DHEA and all bioactive sex steroids is essential to further understand the importance of this precursor steroid in various physiopathological processes. The present data also suggest that DHEA is converted predominantly to DHEA-S and androgens in the female cynomolgus monkey and that the metabolism to androgens could benefit from the high concentration of DHEA-S formed through the first hepatic pass. Further studies on the respective contribution of the liver and other peripheral tissues to the metabolism of DHEA are required to precisely assess the mechanisms involved in the physiological effects of long term hormone replacement therapy with DHEA in humans.
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Footnotes |
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Abbreviations: ADT-G, Androsterone glucuronide; AUC, area under the curve; BLQ, below the limit of quantification; Cmax and Cmin, maximum and minimum serum concentrations measured during the study period; CR, conversion ratio; DEX, dexamethasone; DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate; DHT, dihydrotestosterone; 5-diol, androst-5-ene-3ß,17ß-diol; 4-dione, androstenedione; DMSO, dimethylsulfoxide; E1, estrone; E2, estradiol; MCR, metabolic clearance rate; OVX, ovariectomized or ovariectomy; PO, oral(ly); testo, testosterone; UGT, uridine diphosphate-glucuronosyltransferase.
Received January 7, 2003.
Accepted May 29, 2003.
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References |
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4-androstenedione, dehydroepiandrosterone and oestradiol-17ß in the crab-eating monkey (Macaca fascicularis) from birth to adulthood. J Reprod Fertil 74:347–359[Abstract]
-reduced C19 steroid glucuronides in primates, rodents, and domestic animals. Am J Physiol 271:E348–E353
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