DHEA) on Urinary Steroid Metabolites in Males and Females

Steroids 65 (2000) 98–102

Inﬂuence of oral dehydroepiandrosterone (DHEA) on urinary steroid metabolites in males and females

Frank Calliesa,*, Wiebke Arlta, Lothar Siekmannb, Doris Hu¨blerc, Frank Bidlingmaierb, Bruno Allolioa

aDepartment of Endocrinology, University of Wuerzburg, Josef–Schneider–Str. 2, 97080 Wuerzburg, Germany bInstitute of Clinical Biochemistry, University of Bonn, Bonn, Germany cJenapharm GmbH & Co. KG, Jena, Germany

Received 1 June 1999; received in revised form 29 July 1999; accepted 3 August 1999

Abstract

Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of potential beneficial effects and exerts its action mainly via peripheral bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been shown by us and others to restore low endogenous serum DHEA concentrations to normal youthful levels followed by an increase in circulating androgens and estrogens. As the hepatic first-pass effect may lead to a non physiological metabolism of DHEA after oral ingestion we studied the influence of two single DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly males [age 58.8 Ϯ 5.1 years (mean Ϯ SEM)] with endogenous DHEAS levels Ͻ1500 ng/ml and in 9 healthy females (age 23.3 Ϯ 4.1 years) with transient suppression of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4 ϫ 0.5 mg/day/4 days). Urinary steroid profiles in the elderly males were compared to the steroid patterns found in 15 healthy young men (age 28.9 Ϯ 5.1 years). In the females the results were compared to their individual baseline excretion without dex pretreatment. Urinary steroid determinations were carried out by semiautomatic capillary gas-liquid chromatography. In both genders DHEA administration induced significant increases in urinary DHEA (females: baseline vs. 50 mg vs. 100 mg: 361 Ϯ 131 vs. 510 Ϯ 264 vs. 1541 Ϯ 587 ␮g/day; males: placebo vs. 50 mg vs. 100 mg: 434 Ϯ 154 vs. 1174 Ϯ 309 vs. 4751 Ϯ 1059 ␮g/day) as well as in the major DHEA metabolites androsterone (A) and etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its metabolites only slightly above baseline levels found in young females and in young men, respectively, whereas 100 mg induced clearly supraphysiological values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA) were not significantly different between elderly males vs. young male volunteers and young healthy females versus their individual baseline levels. In conclusion, an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile in subjects with DHEA deficiency without evidence for a relevant hepatic first-pass effect on urinary metabolites. © 2000 Elsevier Science Inc. All rights reserved.

Keywords: Dehydroepiandrosterone (DHEA); Urinary steroid excretion; Androsterone; Etiocholanolone; Chromatography; Adrenal insufﬁciency

1. Introduction age [1]. Recent studies suggest that DHEA replacement may have beneficial effects on well-being in aging males and Dehydroepiandrosterone (DHEA) and its sulfate ester females [2]. Thus, DHEA replacement may also be useful in (DHEAS) are the most abundant steroids in the human patients with adrenal insufficiency, who suffer from chronic circulation, but their physiological role remains to be fully DHEA deficiency. It was reported that these patients have elucidated. Both DHEA and DHEAS show a characteristic impaired quality of life despite standard replacement ther- age-related pattern of serum levels peaking between the apy with glucocorticoids and mineralocorticoids [3,4]. second and third decade of life and then declining to levels However, only limited data are available on the optimum of about 10 to 20% of peak concentrations during advanced replacement dose of DHEA for these patient groups. A daily dose of 50-mg DHEA has been shown by us [4,5] to restore * Corresponding author. Tel.: ϩ49-931-201-3122; fax: ϩ49-931-201- low endogenous serum DHEA concentrations to normal 2283. youthful levels followed by an increase in circulating an- E-mail address: [email protected] (F. Callies) drogens and estrogens. The major finding of our studies was

0039-128X/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0039-128X(99)00090-2 F. Callies et al. / Steroids 65 (2000) 98–102 99 that oral DHEA administration influenced the androgen/ Further inclusion criteria were general good health, estrogen ratio in both genders in opposite directions and the absence of chronic disease (including diabetes mel- suggested a metabolic sexual dimorphism. Nevertheless it is litus and arterial hypertension), chronic medication or not known, whether oral administration of DHEA induces a hypogonadism. All subjects had normal blood cell counts nonphysiological urinary steroid pattern due to the hepatic and normal hepatic and renal function parameters. Before first-pass effect. the initiation of the study the protocol had been approved Thus, we studied the influence of two different doses of by the Ethics Committee of the University of Wuerzburg DHEA (50 and 100 mg) on 24-h urinary excretion of steroid and all participants had given their written informed metabolites in elderly males with low endogenous DHEAS consent. levels and in healthy females with transient DHEA suppres- The corresponding pharmacokinetic data of serum hor- sion induced by dexamethasone (dex) pretreatment. mone concentrations after oral DHEA treatment have been published elsewhere [4,5].

2. Experimental 2.2. Samples

At each cycle, 24-h urine specimens were collected from 2.1. Subjects and study design each volunteer. The volunteers were carefully instructed to collect 24-h urine from 9:00 a.m. at day one to 9:00 a.m. of 2.1.1. DHEA-substitution in elderly male volunteers the following day. 2.1.1.1. Subjects. Fourteen healthy elderly men [age 58.8 Ϯ In the 15 healthy young men only a single collection of 5.1 years (mean Ϯ SEM), body mass index (BMI) 25.5 Ϯ 24-h urine without any medication was performed. 1.5 kg/m2] participated in this study. To study the pharmacokinetics and biotransformation of orally ingested DHEA 2.3. DHEA preparation in these elderly males we compared their urinary steroid profiles to those found in 15 healthy young male volunteers The capsules containing 50 mg DHEA as well as the (age 28.9 Ϯ 5.1 years, BMI 24.1 Ϯ 8.9 kg/m2). placebo capsules were both provided by Jenapharm GmbH & Co. KG (Jena, Germany). As determined by high-perfor- 2.1.1.2. Protocol I. The study was performed in a single- mance liquid chromatography (HPLC), the mean DHEA Ϯ dose, randomized, cross-over design. All men had baseline content of the capsules was 49.3 0.20 mg with an in vitro serum DHEAS concentrations Ͻ 4.1 ␮mol/l (Ͻ1500 ng/ release of 82.2% within 45 min. ml). On three occasions either placebo, 50 mg or 100 mg of DHEA were administered orally at 9:00 a.m. in randomized 2.4. Hormone assays order. To define a suitable replacement dose of oral DHEA for elderly males we compared their urinary steroid profiles 2.4.1. Methods to those found in 15 healthy young male volunteers. In these For the determination of urinary steroids we used a 15 healthy young men only a single collection of 24-h urine, previously described semiautomatic capillary gas-liquid without any medication, was performed. chromatographic method [6]. The following metabolites had been measured: DHEA, Androsterone (A), 16␣DHEA, ␤ 2.1.2. DHEA substitution in young female volunteers Etiocholanolone (Et), -Cortol, THF (Tetrahydrocortisol), ␣-THF, THE (Tetrahydrocortisone), TH-DOC (Tetra-des- 2.1.2.1. Subjects. Nine healthy female volunteers (age oxycorticosterone), THS (Tetrahydro-11-desoxycortisol), 23.3 Ϯ 4.1 years, BMI 22.5 Ϯ 1.8 kg/m2) were included in and cortolones (␣ and ␤). this study. 2.4.2. Enzymatic hydrolysis 2.1.2.2. Protocol II. The study was performed in a single- 24-h urine collections were adjusted to pH 4.0 with dose, randomized, cross-over design. All female subjects acetic acid and stored at Ϫ20°C. Of the 24-h urine samples, were studied during the early follicular phase of four 10 ml were adjusted to pH 4.5 and incubated with 0.15 ml subsequent cycles. Cycle 1 served as baseline. Preceding glucuronidase-arylsulfatase from helix pomatia (Boehr- the study days during cycles 2 through 4, all subjects inger, Mannheim, FRG). The released steroids were ex- were pretreated with oral dex (4 ϫ 0.5 mg daily for 4 tracted with 20-ml ether, washed with 2 ml concentrated days). On study Days 2 through 4, either placebo or 50 or sodium carbonate and evaporated to dryness. 100 mg DHEA was administered orally at 9:00 a.m. All women had baseline serum concentrations of DHEA(S), 2.4.3. Derivatization androstenedione, and/or testosterone within the normal Trimethylsilylenol ethers were formed according to a range. All women had a regular menstrual cycle and none method described by Chambaz and Egger et al. [7,8]. For of them was on oral contraceptives or other medication. derivatization about 1 mg dry potassium acetate crystals, 100 F. Callies et al. / Steroids 65 (2000) 98–102

Table 1 Mean urinary excretion rates (␮g/24 h, Ϯ SEM) of steroid metabolites after administration of 50 and 100 mg DHEA to elderly males compared to controls (ϭ young healthy male volunteers)

Hormones (␮g/24 h) Control group Baseline 50 mg DHEA 100 mg DHEA DHEA 798 Ϯ 123 434 Ϯ 154 1174 Ϯ 309* 4751 Ϯ 1059*** Androsterone (A) 3086 Ϯ 250 1287 Ϯ 203*** 5346 Ϯ 716*** 10845 Ϯ 1187*** Etiocholanolone (Et) 2834 Ϯ 324 1154 Ϯ 310*** 4525 Ϯ 627*** 7847 Ϯ 709*** 16␣ DHEA 642 Ϯ 94 139 Ϯ 23*** 797 Ϯ 185** 2194 Ϯ 291*** Ratio A/DHEA 5.3 Ϯ 0.9 7.1 Ϯ 1.3 8.5 Ϯ 2.2 4.3 Ϯ 1.1 Et/DHEA 4.6 Ϯ 0.8 4.6 Ϯ 0.7 6.6 Ϯ 1.5 3.0 Ϯ 0.6 16␣ DHEA/DHEA 0.9 Ϯ 0.2 0.8 Ϯ 0.2 1.3 Ϯ 0.4 0.8 Ϯ 0.2

* P Յ 0.05. ** P Յ 0.01. *** PՅ 0.001.

100 ␮l N-methyl-N-trimethyl-silyltriﬂuoroacetamide, and 3. Results 50 ␮l pyridine were added to the very dry steroid extracts followed by a 12-h incubation at 60°C. 3.1. Elderly male volunteers

2.4.4. Capillary gas-liquid chromatography The results of urinary baseline levels of DHEA and its Of this reaction mixture, 1 or 2 ␮l are transferred with a metabolites as well as the influence of 50 and 100 mg Hamilton syringe into self-made glass tubes measuring DHEA on urinary DHEA metabolites are given in Table 1. 1.2 ϫ 3 mm (outer diameter). In these tubes up to 20 Compared to healthy young men the elderly males had a samples can be dried at the same time in an rotary pump significantly lower excretion of the main DHEA metabolites vacuum at room temperature. Thereafter, the sample tubes A(P Ͻ 0.0001) and Et (P Ͻ 0.001). Although excretion of are transferred to the sample plate of an auto solid injector DHEA was also lower in elderly men, the difference did not (CE-Instruments, Milan, Italy). reach statistical significance (P ϭ 0.07). The sample plate was loaded with one blank, four stan- After oral administration of DHEA, the major metabo- dard steroid mixtures and up to 15 urinary sample tubes. lites of DHEA (A, Et) significantly increased in a dose- The cGLC works fully automatically and about1his dependent manner. The administration of 50 mg DHEA led needed to complete one sample. to a significant increase of DHEA, A, and Et slightly above the excretion found in young healthy males, whereas 100 2.4.5. Instrumentation of cGLC mg of DHEA clearly induced supraphysiological values. GLC apparatus: Mega, CE-Instruments; capillary col- The ratios of urinary DHEA metabolites (A/DHEA, Et/ umn: 35-meter glass column OV 101 (inner diameter 0.22 DHEA, and 16␣DHEA/DHEA) were not significantly dif- mm; Chrompack); inlet temperature: 350°C; detector: FID, temperature 300°C; temperature program: 190 to 290°C, ferent between the elderly males at baseline and after 50 mg 2°C/min; carrier gas: helium 60 kPa; integrator: Spectra in comparison to the young male volunteers. Mean baseline Ϯ Ϯ Physics, model 4100. A/DHEA ratio was 7.15 1.30 (mean SEM) for elderly Ϯ The intra-assay coefficient of variation (CV) for the males vs. 5.32 0.96 for young healthy males, Et/DHEA Ϯ Ϯ Ϯ urinary steroids A, Et and 16␣DHEA was 3%, 6%, and 4.65 0.79 vs. 4.62 0.82 (mean SEM), and 10%, respectively. The CV for cortisol metabolites (TH- 16␣DHEA/DHEA 0.86 Ϯ 0.22 vs. 0.95 Ϯ 0.20. After 50 DOC, THS, ␣-/␤-cortolone, THE, ␤-cortol, THF and mg DHEA, the mean A/DHEA was 8.57 Ϯ 2.29, Et/DHEA ␣-THF) ranged between 5% and 15%. The corresponding 6.62 Ϯ 1.51, and 16␣DHEA/DHEA 1.36 Ϯ 0.44. inter-assay CV was 7% for A, 12% for Et, and 20% for The glucocorticoid metabolites (THE, THF,␣-/␤-cor- 16␣DHEA. The inter-assay CV for cortisol metabolites tolone) were not altered by DHEA administration. ranged between 11 and 30%. 3.2. Young female volunteers 2.5. Statistics The results of dex suppression and the influence of 50 All results are reported as the mean Ϯ SEM. Compari- and 100 mg DHEA on urinary DHEA metabolites are given sons between groups (baseline and after DHEA treatment) in Table 2. were performed by Student’s unpaired t-test for the males Pretreatment with dex led to a significant suppression of and paired t-test for the females. P Յ 0.05 was considered the urinary metabolites of DHEA (androsterone (A), and as statistically significant. etiocholanolone(Et)) with a similar effect on the urinary F. Callies et al. / Steroids 65 (2000) 98–102 101

Table 2 Mean urinary excretion rates (␮g/24 h, Ϯ SEM) of steroid metabolites at baseline (ϭ without dex pretreatment), after preceding dex treatment (4 ϫ 0.5 mg/day for 4 days) and placebo/50 mg DHEA or 100 mg DHEA in females

Hormones Baseline Dex ϩ placebo Dex ϩ 50 mg Dex ϩ 100 mg (␮g/24 h) DHEA DHEA DHEA 361 Ϯ 131 92 Ϯ 56 510 Ϯ 264 1541 Ϯ 587* Androsterone (A) 1095 Ϯ 256 458 Ϯ 216* 1974 Ϯ 302** 4315 Ϯ 636*** 16␣ DHEA 654 Ϯ 215 209 Ϯ 103* 820 Ϯ 420 1805 Ϯ 521** Etiocholanolone (Et) 1358 Ϯ 333 559 Ϯ 179* 2458 Ϯ 388** 6132 Ϯ 1226*** Ratio A/DHEA 6.6 Ϯ 1.7 14 Ϯ 8.1 7.5 Ϯ 2.7 Et/DHEA 9.0 Ϯ 2.68 21 Ϯ 11 15.0 Ϯ 6.9 16␣ DHEA/DHEA 0.4 Ϯ 0.19 0.1 Ϯ 1.3 3.0 Ϯ 1.13

Statistical differences are calculated in comparison to baseline values. * P Յ 0.05. ** P Ͻ 0.01. *** P Ͻ 0.001. excretion of cortisol metabolites (THE, THF, A-THF, ␣-/ DHEA once daily restored DHEA and DHEAS concentra- ␤-cortolones, ␤-cortol). tions into the normal range [10]. A dose of 50-mg DHEA induced an increase in urinary Although endogenous DHEA is secreted by the adrenal DHEA excretion (to a mean of 41% above baseline), gland into the systemic circulation [11], oral DHEA is whereas 100 mg DHEA lead to a fourfold increase of subject to a first-pass effect in the liver [12]. As the liver DHEA excretion significantly above baseline levels. plays an important role both in biotransformation and me- Similarly after 50 mg DHEA, the excretion of other tabolism of DHEA [13], the urinary steroid pattern is likely urinary DHEA metabolites like A and Et increased to values to be influenced by the route of DHEA administration. We slightly above those found in the females at baseline, hypothesized that a significant first pass metabolism should whereas 100 mg induced marked supraphysiological steroid lead to an increase in the ratio of the metabolites andros- excretion. terone (A) and etiocholanolone (Et) to DHEA. In fact an The ratios of urinary DHEA metabolites (A/DHEA, Et/ increase in the ratios of A/DHEA and Et/DHEA was ob- DHEA, 16␣DHEA/DHEA) were higher after 50 mg DHEA, served after single dose of 50-mg DHEA suggesting the but not significantly different from baseline values. Mean increased generation of DHEA metabolites in the liver due baseline A/DHEA was 6.67 Ϯ 1.70 (mean Ϯ SEM) vs. to a first pass effect. However, possibly due to the small 14.85 Ϯ 8.10 after 50 mg DHEA (P ϭ 0.07), Et/DHEA sample size, this increase was not significant and was not 9.06 Ϯ 2.68 vs. 21.65 Ϯ 11.50 (P ϭ 0.08), and 16␣DHEA/ seen after a dose of 100-mg DHEA, suggesting that with our DHEA 0.41 Ϯ 0.19 vs. 0.17 Ϯ 1.35 (P ϭ 0.93). DHEA preparation the hepatic first pass effect is of minor The excretion of glucocorticoid metabolites (THE, THF, importance. ␣-/␤-cortolone) was significantly suppressed by dex and not An important aspect of DHEA administration is the rapid altered by DHEA administration. conversion to DHEAS, which can be converted back to DHEA by peripheral sulfatases [14]. As a result, a single dose of DHEA leads not only to a rapid increase in DHEAS 4. Discussion and active sex steroids but also to a lasting rise in circulating DHEA [4,5]. In previous studies, different routes of DHEA The major finding of our study is, that in elderly males administration and different pharmaceutical formulations with low endogenous DHEAS and in dex-suppressed young were used to reduce or avoid the hepatic first-pass effect, females, oral administration of 50 mg DHEA restored uri- aiming at an increased DHEA/DHEAS ratio and avoiding nary excretion of DHEA and its metabolites to levels ob- rapid biotransformation into androgens [12]. Transvaginal served in healthy young subjects. In contrast, a single oral [15] and transdermal [16] administration of DHEA induced dose of 100 mg DHEA led to significantly supraphysiologi- a higher DHEA/DHEAS ratio. However, the clinical signif- cal urinary excretion rates of DHEA, A, and Et. These icance of these observations remains to be elucidated. In results correspond to the pharmacokinetic data of serum fact, hepatic biotransformation to DHEAS after oral admin- hormone concentrations after oral DHEA [2,4,5,9], support- istration may be useful in DHEA(S) deficiency, as this ing the view that 30 to 50 mg of oral DHEA can be conversion is comparable to the adrenal secretory pattern, considered a suitable substitution dose for patients with where DHEAS is the major secretory product. As DHEAS DHEA deficiency. Accordingly, in a recent study in women has a long half-life, it could serve as an important circulat- with adrenal insufficiency chronic administration of 50 mg ing pool from which other steroids are generated [17]. The 102 F. Callies et al. / Steroids 65 (2000) 98–102 generation of highly virilizing androgens (e.g. testosterone) sterone (DHEA) in elderly males: significant increase in circulating by a hepatic first-pass effect after oral administration of estrogens. J Clin Endocrinol Metab 1999;84:2170–6. 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