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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 146-150
Copyright © 2001 by The Endocrine Society

Original Studies

Urinary Nandrolone Metabolites of Endogenous Origin in Man: A Confirmation by Output Regulation under Human Chorionic Gonadotropin Stimulation

Yves Reznik, Louis Dehennin, Christine Coffin, Jacques Mahoudeau and Pierre Leymarie

Service d’Endocrinologie (Y.R., C.C., J.M.) and Laboratoire de Biochimie B (P.L.) Centre Hospitalier Universitaire Côte de Nacre 14033 Caen; and Laboratoire de la Fédération Nationale des Courses Françaises (L.D.), 92290 Chatenay-Malabry, France

Address all correspondence and requests for reprints to: Y. Reznik, M.D., Department of Endocrinology, Centre Hospitalier Universitaire Côte de Nacre, 14033 Caen Cedex, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
19-Nortestosterone (nandrolone) is an anabolic steroid compound widely used as a doping agent by athletes. The analysis of its urinary metabolites, 19-norandrosterone (NA) and 19-noretiocholanolone (NE) glucuronides, allows the detection of surreptitious administration of nandrolone in sport. A threshold concentration at 2 µg/L urinary nandrolone metabolites is advocated by the International Olympic Committee for the detection of doping, but some controversy concerning the validity of this threshold arose from the demonstration of endogenous production of nandrolone in mammals, including humans. The regulation of human nandrolone production and its contribution in vivo to the process of aromatization remain unknown. In the present study 10 healthy men were successively submitted to insulinic stress and gonadal stimulation by hCG administration. Urinary NA and NE concentrations were quantified by gas chromatography-mass spectrometry. NA was detected in basal urine samples from all subjects, with a mean urinary excretion rate (UER) of 3.17 ± 0.35 ng/h, whereas NE was detected in 4 of 10 (UER range, 0.8–4.7 ng/h). Insulinic hypoglycemia did not significantly modify mean NA UER despite random intraindividual variations between timed urine collections. After hCG administration, NA UER increased by 250% (P < 0.01) and estradiol (E2) UER by 260% (P < 0.001). The maximum NA concentration obtained after stimulation was 0.43 µg/L. NA UER, plasma E2, and E2/T ratio peaked on day 1 after hCG administration, whereas plasma T peaked later on day 3. NA UER correlated with plasma E2 (r = 0.61; P < 0.001) and E2/T (r = 0.51; P < 0.001), but not with plasma T. In conclusion, insulinic stress did not significantly alter nandrolone metabolism, whereas the effect of hCG was a stimulation of NA excretion in all subjects, which constitutes strong support for the endogenous origin of low basal NA excretion. The comparative kinetics of NA UER, plasma E2, and E2/T ratio suggest a contribution of the aromatase process to nandrolone biosynthesis in man.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
19-NORTESTOSTERONE (nandrolone) has been widely used over the past 30 yr to improve the physical performances of race horses and athletes despite its ban by sport federations and racing authorities. The need for an efficient screening of anabolic steroids in doping control was a strong impetus for the development of high performance analytical techniques able to detect trace amounts of steroids in blood and urine. In that respect, gas chromatography-mass spectrometry (GC-MS) is considered the gold standard for the quantitative analysis of nandrolone in blood (1) and its metabolites 19-norandrosterone (NA) and 19- noretiocholanolone (NE) in urine (2, 3, 4). Over the past 2 yr, screening for misuse of nandrolone by athletes has been a subject of controversy and discussion, as data have been reported on the presence of norandrogens of endogenous origin in several mammalian species including the human.

Large amounts of nandrolone and 19-norandrostenedione were identified in follicular fluid from equine (5, 6) and human species (7), and nandrolone was detected in plasma from pregnant (1) and male (8) horses. In vitro experiments have demonstrated the synthesis of norandrogens by equine placental explants and porcine granulosa cells, involving the aromatase enzyme complex (9, 10). Norandrogens are converted into estrogens by equine and human placental aromatase (11) and by equine testicular aromatase (8), suggesting their involvement as a minor intermediate in the aromatization process.

Recently, trace levels of NA were quantified in urine from healthy men (3, 4), raising the possibility that detection of nandrolone metabolite levels above the threshold of 2 µg/L, established by the International Olympic Committee (IOC), could lead to misinterpretation in athletes who deny any anabolic steroid administration.

We therefore conducted this study to test the hypothesis that urinary excretion of nandrolone metabolites might be enhanced after the metabolic stress of insulin-induced hypoglycemia or after testicular stimulation by hCG administration. This study also gave us the opportunity to analyze the kinetics of androgen and estrogen secretion in parallel with nandrolone metabolite excretion under stimulating conditions and thereby to evaluate in vivo the contribution of the aromatization process to the production of norandrogens.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Ten men volunteered for and gave informed consent to the study after its approval by the local human studies committee. The physical and gonadal characteristics of the volunteers are presented in Table 1Go. All were healthy and had not suffered from any severe disease during the past 6 months. They practiced moderate recreational sport activities (1–4 h/week), and denied any previous drug or anabolic steroid abuse. Their gonadal status was normal, and their lean body mass measured by bioimpedance analysis was within the normal range.


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  		Table 1. Baseline anthropometric and gonadal characteristics in 10 normal male volunteers

 
Endocrine tests

Subjects were submitted to two successive endocrine tests, each performed after an overnight fasting period. An iv catheter was placed 1 h before the test to avoid puncture stress. Subjects were given an iv insulin injection (0.1 IU/kg regular insulin) at 0800 h, and blood samples were collected before injection and at 15, 30, 60, 90, 120, and 180 min after injection for the determination of glucose, cortisol, testosterone (T), and estradiol (E2) plasma levels. Baseline urine was collected between 0800–1200 h the day preceding the test and at 0–2, 2–4, and 4–10 h following insulin administration for the determination of NA, NE, and free cortisol. Two to 4 weeks later, subjects were given 5000 IU hCG (Gonadotrophine Chorionique Endo, Organon, Puteaux, France), im, at 0800 h. Blood samples and 0800–1200 h urine fractions were collected before injection (the day preceding hCG injection for baseline urine) and 24 h (day 1), 48 h (day 2), and 72 h (day 3) after injection for the determination of T and E2 plasma levels and NA, NE, and E2 urinary levels.

Plasma glucose and hormone assays

Blood samples were drawn in dry tubes, centrifuged at 3000 x g, and stored at -20 C until analysis. Plasma glucose was measured by glucose oxidase (kit from Roche Molecular Biochemicals for BM/Hitachi 717, Indianapolis, IN). Plasma and urinary cortisol levels were measured with a RIA kit purchased from INCSTAR Corp. (Stillwater, MN). Cortisol intra- and interassay variabilities were 7% and 9%, respectively. T and E2 plasma concentrations and E2 urinary concentrations were measured by RIA (Biomérieux, France) after ether extraction. Intra- and interassay variabilities were 7% and 9% for testosterone and 5% and 17% for estradiol, respectively.

Urinary steroid assays

Urine aliquots were stored at -20 C until analysis. The method for quantitation of subnanogram amounts of NA and NE was described in detail previously (3). Briefly, after solid phase extraction, conjugate hydrolysis by ß-glucuronidase from Escherichia coli, and extensive purification by ion exchange and partition chromatography, NA and NE urinary concentrations were quantified by GC-MS using stably labeled NE as an internal standard. NA and NE were analyzed in a single GC-MS run by monitoring ion masses 405, 408, 432, and 434 of the corresponding respective bis(trimethylsilyl) derivatives. The quantitative detection limits for NA and NE were 0.01 and 0.04 µg/L, respectively. Concentrations are expressed as micrograms of free steroid per L. As timed urine collections were made, urinary excretion rate (UER) expression as nanograms of free steroid per h was preferred.

Statistical analysis

Data were analyzed by repeated measures ANOVA, and significance of differences was determined by post-hoc tests. Correlation coefficients were calculated by simple regression analysis or Spearman’s rank test for small size samples. Data are presented as the mean ± SEM, and statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal excretion of NA and NE

NA was detected in baseline urine samples from all subjects at a concentration range 0.01–0.14 µg/L (mean, 0.07 ± 0.01 µg/L). NE was detected in 4 of 10 subjects at a concentration range of 0.02–0.07 µg/L. The mean NA UER was 3.17 ± 0.37 ng/h.

Hypoglycemic stress

After a single iv insulin administration, all subjects experienced a symptomatic hypoglycemic episode, with the mean plasma cortisol level rising significantly (P < 0.001) above 200 µg/L. Mean T and E2 plasma levels dropped by 30% and 21%, respectively, from baseline levels (P < 0.001; Fig. 1Go). The free cortisol UER rose 3.4-fold from the baseline level. No significant change in mean NA UER was observed (Fig. 2Go) despite random intraindividual variations between urine samples collected at different times after insulin administration (data not shown). The maximum urinary NA concentration detected after insulinic stress was 0.19 µg/L, whereas NE was detected in trace amounts in only one subject.



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  		Figure 1. Effect of an iv injection of 0.1 IU/kg regular insulin on mean glucose, cortisol, T, and E2 plasma levels in 10 normal men. •, Glucose; {square}, cortisol; {triangleup}, T; {blacksquare}, E2. *, P < 0.001 vs. baseline.

 


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  		Figure 2. Effect of an iv injection of 0.1 IU/kg regular insulin on the mean excretion rate of NA and cortisol in timed urine collections from 10 normal men. *, P < 0.001 vs. baseline.

 
hCG stimulation test

After a single im hCG injection, mean plasma E2 and T levels rose by 315% and 86%, respectively (P < 0.001), with the E2 peak occurring on day 1 and the T peak occurring on day 3 after hCG administration (Fig. 3Go). E2 UER elicited a 160% rise above baseline (P < 0.001; Fig. 4Go). The mean E2/T plasma ratio rose by 200% (P < 0.001) and peaked on day 1 after hCG administration (Fig. 3Go). NA UER was stimulated by hCG in all subjects, and mean NA UER rose by 250% (P < 0.01) above the baseline 1 day after hCG administration (Fig. 4Go). NE was detected in baseline urine from four subjects, and rose in all four by 57–240% after hCG administration (data not shown). The maximum urinary NA and NE concentrations detected after hCG stimulation were 0.43 and 0.20 µg/L, respectively. A highly significant positive correlation was observed between NA UER, on the one hand, and plasma E2 (P < 0.001) and E2/T ratio (P < 0.001), on the other hand. No correlation was observed between NA UER and plasma T (Fig. 5Go).



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  		Figure 3. Effect of an im injection of 5000 IU hCG on mean T and E2 plasma levels and E2/T ratio in 10 normal men. •, T; {square}, E2; {triangleup}, E2/T x 1000. *, P < 0.001 vs. baseline.

 


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  		Figure 4. Effect of an im injection of 5000 IU hCG on the mean excretion rate of E2 and NA in timed urine collections from 10 normal men. *, P < 0.01; **, P < 0.001 (vs. baseline).

 


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  		Figure 5. Relation between UER of NA and plasma T, E2, and E2/T ratio in 10 normal men during a hCG stimulation test.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study confirms the presence of nandrolone metabolites in timed urine collections from 10 healthy men free of anabolic steroid supply. In baseline urine samples, NA was detected in all subjects at subnanomolar concentrations, whereas NE was detected in only half of the subjects. These data are in accordance with recent findings of trace amounts of NA in the urine from healthy volunteers (3, 4). These studies were conducted with GC-MS methods, which ensure a highly sensitive and specific detection of nandrolone metabolites.

A few studies in the human have mentioned picomolar levels of circulating nandrolone (12, 13, 14), measured by RIA without validation by a reference GC-MS method. Rising plasma levels of nandrolone (1) and its urinary metabolites (Dehennin, L., unpublished data) have been observed in women throughout pregnancy, but no nandrolone could be detected in plasma from cycling women or men (1). Very recently, urinary NA excretion has been demonstrated in cycling women, with peak levels at the time of ovulation (15).

After oral administration of nandrolone to seven men (1.5 µg/kg BW), only plasma levels of norandrosterone glucuronide could be quantified in the 0.5–5 nmol/L range (Dehennin, L., unpublished data). Therefore, the MCR and liver first pass metabolism of nandrolone are probably very high.

Identification of nandrolone urinary metabolites of endogenous origin in man is of critical importance for the interpretation of positive doping tests, as highlighted recently in athletes who denied any drug administration. Only scarce data are available concerning variations in endogenous nandrolone secretion and its regulation, but intense physical effort in athletes was reported to raise NA concentrations by 2- to 4-fold in spot urine collections without correction for the decrease in volume diuresis (4). We therefore investigated the variations in NA and NE urinary excretion following a metabolic stress (i.e. insulinic hypoglycemia) and found no significant variation in mean NA UER despite the occurrence of symptomatic hypoglycemia and activation of the pituitary-adrenal axis in all subjects. A significant drop in mean plasma T and E2 was also observed, in accordance with the report by Elman et al. (16), who observed a fall in T plasma levels after glucoprivation by 2-deoxy-D-glucose infusion in male subjects. This inhibitory effect of stress on the testicular production of androgens is probably mediated by cortisol binding to its Leydig cell receptors or to down-regulation of LH receptor (17, 18). A central mechanism is also advocated, as cortisol (19) as well as CRH and opiatergic pathways (20) were demonstrated to mediate the stress-induced inhibition of LH secretion. In the present study no significant change in norandrogen excretion paralleled the stress-induced decrease in androgen secretion. Our data do not favor an adrenal source of norandrogens, as previously suggested from in vitro studies on dog adrenal tissue (21), but not further confirmed. Norandrogen biosynthesis seems to be linked to the aromatase process (9, 10), and aromatase expression has been demonstrated in porcine, but not normal human, adrenal gland (22, 23).

The regulation of NA and NE excretion was also studied after stimulation by hCG, which led to a sustained and significant increase in NA UER 24 and 48 h after hCG administration, concomitant with a significant rise in E2 UER. T and E2 plasma peaks were dissociated, in accordance with previous studies performed in adult men (24). Interestingly, NA UER, plasma E2, and E2/T ratio exhibited similar patterns of variation, as their peaks occurred on day 1, whereas the T peak occurred on day 3. The highly significant correlation between NA UER and both plasma E2 and E2/T ratio, and the lack of correlation with plasma T are in contrast with the study by Dintinger et al. (8), who observed parallel patterns of 19-nortestosterone and T secretion after in vivo testicular stimulation by hCG in the stallion. Moreover, in their study the E2 peak was observed before androgen and norandrogen peaks.

Our data in man suggest a contribution of the aromatization process to nandrolone production and ensuing metabolism, and therefore reinforce an ancient hypothesis that norandrogen synthesis is linked to the androgen to estrogen conversion (5). In vitro aromatization of 19-nortestosterone by human placental microsomes occurs at a slower rate than for C19 androgens (25), but no data are available for norandrogen aromatization by human testicular tissue. Aromatization of 19-nortestosterone by equine testicular microsomes also occurs at a slow rate in comparison with testosterone (8, 26), suggesting a minor contribution of norandrogens to testicular estrogen production in this species. The testicular origin of nandrolone in the stallion was established by the demonstration of a spermatic veinous to arterial 19-nortestosterone gradient and by the ability of testicular tissues to synthesize norandrogens from androgen precursor in vitro (8).

The effect of hCG on Leydig cell steroidogenesis has been extensively studied. hCG administration to healthy male subjects was shown to induce within 24 h an increase in testicular E2 secretion, which, in turn, was supposed to partly explain the blockade of the 17,20-lyase and 17-hydroxylase activities and consequently limit the initial rise of testosterone, explaining the dissociation of E2 and T secretion patterns (24, 27, 28). In vitro, hCG stimulates aromatization in the mature rat Leydig cell (29), but molecular studies identified no response of the aromatase cytochrome P450 messenger ribonucleic acid to hCG stimulation (30). In vitro data suggest an increase in androgen substrate availability than an increase in aromatase activity during gonadotropin stimulation (30, 31).

Although the hCG-induced nandrolone secretion probably originates from the testis, an extragonadal aromatization of hCG-stimulated androgen substrate of testicular origin may not be excluded. Testicular production of estrogens in man represents only 25% of total estrogen production. Adipose tissue, liver, skin fibroblasts, and brain are other production sites of estrogens (32, 33, 34), because they express aromatase (35), and might therefore contribute to the production of intermediates or by-products of the aromatization process, such as norandrogens.

In conclusion, it appears that all responders to metabolic or hormonal stimulation exhibited NA or NE urinary concentrations below 1 µg/L. Our findings constitute support for the limit of 2 µg/L for NA and NE applied by the International Olympic Committee-accredited laboratories for declaring positive anabolic doping. However, this conclusion has to be taken cautiously in view of the small number of volunteers recruited for this study. Further studies are necessary to determine the individual physiological variations in endogenous nandrolone metabolites under extreme conditions such as sport competition. The demonstration of an in vivo norandrogen regulation and the pattern of steroid secretions under hCG stimulation reinforce the concept that norandrogen synthesis involves the enzymatic aromatase complex. From the endocrinological point of view, endogenous nandrolone and its metabolites probably have limited biological effects. Their interest is actually related to doping control, and it seems therefore of paramount importance to further characterize endogenous nandrolone metabolism in man.


   Acknowledgments
 
We are indebted to the volunteers for their essential contribution to this study, and to Raymonde Golba and Francoise Poiblaud for their excellent technical assistance.

Received November 10, 1999.

Revised June 16, 2000.

Revised September 5, 2000.

Accepted September 8, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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