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Blood and testicular extracts of the scincid lizard Tiliqua (Trachydosaurus) rugosa were analyzed using thin-layer, column, and high-performance liquid chromatography. The major androgens isolated were epitestosterone, testosterone, and androstenedione. Epitestosterone was characterized by chromatography in several systems, and by derivative formation. Epitestosterone was further identified in testicular extracts by gas chromatographymass spectrometry. Immunoreactive material was detected in tissue extracts using an antiserum specific to epitestosterone. The maximum concentration of epitestosterone in blood, measured by radioimmunoassay, was four times that of testosterone (approximately 900 and 200 nmol/l, respectively). Epitestosterone could not be detected in the blood of intact females and the concentration of this steroid was low in castrate males. The maximum testicular concentrations (pmol/testis) were 390 (nonincubated) and 2050 (incubated) for epitestosterone, and 2025 (nonincubated) and 1040 (incubated) for testosterone. Both plasma and testicular concentrations showed considerable seasonal variation. The identification of endogenous epitestosterone confirms the results of earlier investigations using radioactive substrates. The occurrence of this steroid as a major product of the testis in T. rugosa is discussed in relation to androgens in reptiles and other vertebrates.
A purified rat hepatic monooxygenase system containing cytochrome P-450b oxidizes testosterone to androstenedione and 16 alpha- and 16 beta-hydroxytestosterone at approximately equal rates. The metabolism of epitestosterone by the same system is characterized by a marked stereoselectivity in favor of 16 beta-hydroxylation (4- to 5-fold relative to 16 alpha-hydroxylation), formation of 15 alpha-hydroxyepitestosterone, and a rate of androstenedione formation which is three to five times higher than that observed with testosterone. Apparent Km values for 16 alpha- and 16 beta-hydroxylation and androstenedione formation are 20-30 microM with either substrate. Mass spectral analysis of the androstenedione formed from [16,16-2H2]testosterone and [16,16-2H2] epitestosterone indicates essentially complete retention of deuterium, thereby ruling out a mechanism of androstenedione formation via C-16 hydroxylation followed by loss of water and rearrangement. Mass spectral analysis of the C-16 hydroxylation products from incubations of testosterone or epitestosterone in 18O2 shows essentially complete incorporation of 18O (greater than 95%). Androstenedione formed from testosterone is enriched in 18O only 2-fold (5-8%) over background, while the androstenedione formed from epitestosterone shows 84% enrichment. Kinetic experiments utilizing [17-2H]testosterone and [17-2H]epitestosterone as substrates indicate that cleavage of the C-17 carbon-hydrogen bond is involved in a rate-limiting step in the formation of androstenedione from both substrates. Taken together, our results indicate that androstenedione formation from epitestosterone proceeds exclusively through the gem-diol pathway, while androstenedione formation from testosterone may proceed through a combination of gem-diol and dual hydrogen abstraction pathways.
The main purpose of this study was to investigate if the specificity of the binding of testosterone to plasma proteins could be defined as a preferential binding of this steroid over epitestosterone. The amount of testosterone that is specifically bound was calculated using the formula: (see article) concentration, where "Ri" is the ratio (14C) testosterone: (3H) epitestosterone in plasma prior to centrifugation, "Ru" is the isotope ratio in the protein-free supernatant obtained after ultracentrifugation (149,000 x g, at 0 C, for 18 h) and "T concentration" is the testosterone concentration in plasma resulting from addition of (14C) testosterone, the endogenous steroids having been removed by preliminary charcoal extraction. The theoretical separation of the binding sites for testosterone into two populations, one non-specific with no preference for testosterone over epitestosterone, and another with absolute specificity for testosterone over its physiologically inactive stereoisomer, proved to be useful. Ovalbumin was found to be an example for non-specific, non-preferential binding. Determination of the ratio (14C) testosterone: (3H) epitestosterone in the successive fractions of various ultracentrifuged preparations showed a small but significant preference for (14C) testosterone by human and bovine serum albumin, while alpha1-acid glycoprotein had a preference for (3H) epitestosterone. Saturation curves showed at least two components: the first one, presumably corresponding to TeBG, had a higher affinity and lower capacity. This binding capacity can be accurately determined by extrapolation to the ordinate or the second component, a straight line corresponding to a binding of somewhat lower affinity and much larger capacity.
A radioimmunoassay system for 17 alpha-hydroxy-4-androstene-3-one (epitestosterone) was developed and evaluated using rabbit antisera against 17 alpha-hydroxy-4-androstene-3-one-3-(O-carboxymethyl)-oxime-bovine serum albumin conjugate, and radioiodinated homologous histaminyl derivative of epitestosterone as a tracer. Two antisera with different specificity were used for radioimmunological determination of epitestosterone in hydrolyzed urine and plasma, respectively. Apparent intrinsic association constants and derived thermodynamic variables for ligand-antibody interaction were measured under various conditions in order to set up an optimal assay protocol. The mean plasma epitestosterone levels for healthy subjects were 0.44 +/- 0.15 nmol.l-1 (means +/- SD) in males and 0.092 +/- 0.056 nmol.l-1 in females. The corresponding concentrations in urine were 320 +/- 70 nmol.l-1 (males) and 273 +/- 100 nmol.l-1 (females).
Epitestosterone, a product of the metabolism of androstenedione by the caprine placenta in vitro, is present in the plasma of the pregnant goat. The maternal concentrations of both epitestosterone and unconjugated oestrogens (mostly oestradiol-17 alpha) in the blood increased before parturition and dropped post partum. Measurement of arteriovenous differences at term indicated that epitestosterone was secreted by the uterus; its production was not dependent on the presence of corpora lutea. It is suggested that the concentration of epitestosterone (+ androstenedione + oestrogens) in maternal plasma may be used as an indicator of placental C-17,20 lyase activity; the slight rise in the concentration of these compounds prepartum suggests a relatively small increase in flow through this enzyme.
Epitestosterone, a 17 alpha-epimer of testosterone is a normal constituent of body fluids in many species including man. It has long been believed that it is devoid of any biological significance. However, it is now demonstrated that in in vivo experiments on castrated male mice it counteracts the action of testosterone on androgen-dependent organs. In vitro experiments show that on the overall antiandrogenicity of epitestosterone participate true antiandrogenic action due to the binding to androgen receptors, strong 5 alpha-reductase inhibiting activity as well as a weak antigonadotropic activity. Epitestosterone is devoid of any embryotoxicity as checked by chick embryo-toxicity screening test.
The action of the endogenous steroid epitestosterone administered to castrated male mice substituted with testosterone propionate is manifested by reduced weight increments and a reduced relative weight of their seminal vesicles and kidneys. Epitestosterone in vitro displaces androgens from their bond with receptors in cytosol from rat prostates and markedly inhibits the testosterone transformation to the more effective androgen dihydrotestosterone. Epitestosterone can be thus defined as a true endogenous antiandrogen; to its action at the receptor level a potent inhibitory effect on 5 alpha-reductase must be added.
Urinary testosterone and epitestosterone were determined in 90 normal healthy women and in 90 women with idiopathic hirsutism, both groups aged between 16 and 46 years. Testosterone and epitestosterone excretion values were above the normal range in 27 of the 90 hirsute women (30%), and these 27 women had much more prominent hair growth than the others. When these results were statistically analysed according to the age groups or for all ages as a whole, they were found to be highly significant (P less than 0.0005). Therefore, it is concluded that the estimation of urinary testosterone and epitestosterone could be meaningfully applied to study the androgen status of hirsute women.
Epitestosterone (17 alpha-hydroxy-4-androsten-3-one), a normal constituent of human plasma and urine, prevents the testosterone induced changes in body weight and in organ weights of seminal vesicles and kidney of castrated male mice. It competes with methyltrienolone in the binding to rat prostate cytosol (Ki = 29.8 nmol.l-1. It inhibits also the activity of 5 alpha-reductase from rat prostate pellet (Ki = 1.2 mumols.l-1). Epitestosterone can be considered as a weak antiandrogen in the term of displacement of androgen from receptor binding and as an efficient inhibitor of 5 alpha-reductase.
Epitestosterone (EpiT) is the 17 alpha-hydroxy epimer of testosterone (T) and a natural steroid metabolite. It has previously been shown to be a 5 alpha-reductase inhibitor. We have studied EpiT as an antiandrogen using the hamster flank organ model. One-centimeter silastic capsules of crystalline T or dihydrotestosterone (DHT) were implanted subcutaneously in female Golden Syrian hamsters to provide continuous androgenic stimulation. After 3 weeks, the pigmented spot was measured and the flank organs were fixed for histologic sectioning. The maximum surface area (SA) from a central section of the sebaceous gland and the diameter of hair follicles were measured using a computerized digitizing tablet. Following T and DHT, respectively, there was a significant increase in pigmented spot size (656/382%), sebaceous gland SA (210/315%), and mean hair follicle diameter (80/56%). A 1-cm capsule of EpiT alone had no androgenic effect. Five- and ten-fold doses of EpiT were implanted with T or DHT. Epitestosterone significantly inhibited the T-dependent stimulation of pigment, sebaceous gland, and hair follicle at either 5- and/or 10-fold excess doses. Additionally, a 10-fold dose of EpiT also inhibited DHT-dependent stimulation of all 3 cutaneous structures. We conclude that EpiT was effective as an antiandrogen and had no intrinsic androgenic activity in the hamster flank organ. It probably functions both as a competitive inhibitor of the androgen receptor and as a 5 alpha-reductase inhibitor. Pigment and sebaceous gland growth were more sensitive than the hair follicle to androgen inhibition by EpiT at the time and doses tested.
5 alpha-reductase activity was investigated in scalp hair roots in 5 patients with 5 alpha-reductase deficiency and in 10 normal volunteers (5 men and 5 women) who served as controls. Metabolism of [3H]testosterone and [3H]epitestosterone was measured under standardized conditions in 1-4 growing (anagen) hair roots. When the mean values of the 5 alpha-reduced metabolites from testosterone (androstanedione and dihydrotestosterone) or from epitestosterone (epidihydrotesterone) were compared in both groups, similar values were observed. However, since most of the hair roots were incubated singly, it could be demonstrated that in two patients 20 respectively 24% of the hair roots showed neither dihydrotestosterone nor epidihydrotestestosterone formation. This did not influence the mean values determined for the whole group perceptibly. Our results support the concept that 5 alpha-reductase deficiency is a genetically heterogenous disorder by demonstrating that the enzyme defect is variously expressed in hair roots of affected individuals.
To obtain more insight into the problem on the concentration of active androgens in the male organism, the diurnal elimination of testosterone, epitestosterone and estrogens in the urine of male patients with cancer of the lung, urinary bladder, larynx and prostate (321 patients), in stage II--III, was estimated. In patients with cancer of the lung and urinary bladder testosterone was found to be lowered, while total estrogens--lowered or unchanged irrespective of age, a relative hyperestrogenization being noted in them. Contrary, in cancer of the larynx and prostate the male hormones were predominating over female ones (hyperandrogenization). In all the examined patients irrespective of the tumor process localization a relative or even absolute predominance of epitestosterone over testosterone was evident.
The metabolism of androgens in the testis of the lizard Tiliqua rugosa has been studied in vitro by incubating cellular homogenates with radiolabeled C19-steroid substrates. The identification 17 beta-oxidoreductase and 3 beta-hydroxysteroid dehydrogenase/isomerase activities. Aromatase, 5 alpha-reductase, and 17 alpha/beta-epimerase activities were not detected. The 17 alpha-oxidoreductase activity was temperature dependent (maximal at 32 degrees), while the 17 beta-oxidoreductase activity was temperature independent. Time yield and dual-label studies indicated that testosterone biosynthesis mainly involves the 4-ene pathway (via androstenedione), whereas the formation of epitestosterone uses both the 4-ene and 5-ene (via 5-androstene-3 beta, 17 alpha-diol) pathways. The function of alternative pathways in androgen biosynthesis is discussed, as is the role of temperature in the intratesticular regulation of androgen production.
Epitestosterone (17 alpha-hydroxy-4-androsten-3-one) inhibits both 17 alpha-hydroxylation and consequent side chain cleavage of the resulting 17 alpha-hydroxyprogesterone in the rat testicular microsomes. The inhibitory activity in terms of the Ki is 2 and 1.5 times as high, respectively, as that of cyproterone acetate.
From Day 268 of gestation till two days after parturition blood samples were collected from the jugular vein of 5 cows with normal and 4 cows with flumethasone induced parturition and centrifuged immediately after sampling. In another experiment blood samples were taken from the jugular and uterine vein of 3 cows during the last week before normal parturition. The dehydroepiandrosterone (DHA) and epitestosterone (ET) concentrations in plasma were measured using radioimmunoassay. In the control group the DHA concentration was in the range of 2 to 5 nmol/l, ET levels varied from 4 to 8 nmol/l before term. In both groups, there was an increase in DHA concentrations during the last periparturient period whereas ET levels increased only after flumethasone induced parturition. The concentrations of both androgens declined after the expulsion of the placenta and they were higher in the uterine vein than in the jugular vein. It is concluded, that both androgens are secreted by the bovine placenta and that the delta 5-pathway of steroidogenesis is active in vivo.
Urinary excretion of testosterone, epitestosterone, androstendion, and 7-keto-dehydroepistendion was studied in 34 healthy men, aged from 20 to 72 years. The maximal excretion of these steroids and observed in men, aged between 20 and 30 years; their reduction was noted with the advance of age.
Testing for illicit self-administration of testosterone by athletes requires quantitative analysis by gas chronomatography-mass spectrometry combined with stable isotope dilution. International Sports Authorities have adopted the ratio of urinary excretions of testosterone and epitestosterone for drug testing. This ratio is required to be under 6. The authors studied the statistical distribution of this ratio in teenage athletes and found that the likelihood of false-positive results is 15/10,000.