Biosynthesis of steroid hormones in a human feminizing adrenal carcinoma
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Pregnenolone-4-14C, progesterone-4-14C, 17α-hydroxyprogesterone-4-14C, 11-deox-ycorticosterone-4-14C, androstenedione-4-14C and testosterone-4-14C were incubated with a homogenate of a feminizing human adrenocortical carcinoma. Estrone, 17β-estradiol were isolated and identified in the phenolic fraction from substrates: pregnenolone, progresterone, androstenedione and testosterone. From androstenedione 19-hydroxyandrostenedione and 19-nortestosterone were identified as metabolic products. Hydroxylation reactions were active for carbons 6, 17 and 21 and appeared to proceed at rates normal to adrenal gland tissue; 16-hydroxylation was not observed. In the tissue homogenates 11β-hydroxylation was not observed; however, it could be demonstrated when supported with the addition of components from bovine adrenocortical mitochondria, thus indicating the presence of only part of the 11β-hydroxylating system.Keywords:
Hydroxylation
Hydroxyprogesterone
Pregnenolone-4-14C, progesterone-4-14C, 17α-hydroxyprogesterone-4-14C, 11-deox-ycorticosterone-4-14C, androstenedione-4-14C and testosterone-4-14C were incubated with a homogenate of a feminizing human adrenocortical carcinoma. Estrone, 17β-estradiol were isolated and identified in the phenolic fraction from substrates: pregnenolone, progresterone, androstenedione and testosterone. From androstenedione 19-hydroxyandrostenedione and 19-nortestosterone were identified as metabolic products. Hydroxylation reactions were active for carbons 6, 17 and 21 and appeared to proceed at rates normal to adrenal gland tissue; 16-hydroxylation was not observed. In the tissue homogenates 11β-hydroxylation was not observed; however, it could be demonstrated when supported with the addition of components from bovine adrenocortical mitochondria, thus indicating the presence of only part of the 11β-hydroxylating system.
Hydroxylation
Hydroxyprogesterone
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Medrogestone, viz., 6,17-dimethylpregn-4,6-diene,3,20-dione (Colprone), a synthetic compound with progestational and antiandrogenic properties, was studied for its effects on the metabolism of pregnenolone and 17 alpha-hydroxypregnenolone by a 10,000 g supernatant fraction of testicular homogenates. This compound inhibited the conversion of pregnenolone to progesterone (91%), 17 alpha-hydroxyprogesterone (83%), delta 4-androstenedione (43%), and testosterone (30%) and the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone (84%), delta 4-androstenedione (56%), and testosterone (38%).
Steroid Metabolism
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ABSTRACT The in vitro biosynthesis of androgenic steroids by surviving human normal and »Stein-Leventhal type« ovarian slices was studied. The tissue slices were incubated in a Krebs-Ringer-phosphate-glucose medium ( p H : 7.4) with pregnenolone, progesterone, 17α-hydroxyprogesterone and androstenedione added as substrates. The incubations were supplied with HCG as cofactor (1000 IU/vessel) and the reactions left to proceed for 6 or 24 hours. After incubation, the medium was extracted with chloroform and transformation products isolated by paper chromatography. Individual substances were characterized by chromatographic mobility studies, preparation of derivatives and spectrophotometric techniques. The following results were obtained: qualitatively no differences could be noted between the metabolic activity of ovarian slices of either origin. Quantitatively, »Stein-Leventhal type« slices showed an accelerated rate of production in all intermediary reactions, especially in the production of androstenedione and testosterone. In addition to the direct intermediaries, four C20 reduced transformation products of progesterone and 17α-hydroxyprogesterone were isolated from experiments involving both normal and micropolycystic ovarian slices.
Hydroxyprogesterone
Steroid biosynthesis
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Hydroxyprogesterone
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Testicular homogenates from rhesus monkeys 1.0, 2.0, 2.5, 2.7, 2.8, 3.0, 7, 8, 8.5 and 9 years of age and those from 33- and 100-day-old rats were incubated with 3H-progesterone, 3H-testosterone and 14C-pregnenolone in the presence of co-factors. In addition, homogenates of testes obtained from patients 3, 4, 5, 7, 15 and 83 years of age at the time of orehiectomy were incubated with 3H-progesterone and 14C-pregnenolone. After incubation, radioactive products were separated and identified by column and paper chromatography with derivative formation and recrystallization to constant specific activity. Testes from monkeys and humans of different ages converted significant amounts (up to 70%) of progesterone and pregnenolone to 17α-hydroxyprogesterone, androstenedione, testosterone, 20α-hydroxypregn- 4-en-3-one and/or 16α-hydroxyprogesterone. Testes of monkeys 1.0–9 years of age converted 1–30% of testosterone to androstenedione. However, no or very small amounts (less than 0.4% of each product) of 5α-reduced metabolites of Δ4–3-ketosteroids were shown to be formed in all monkey and human testes examined. On the other hand, in prepubertal rat testes under the same incubation conditions, conversion of progesterone and testosterone to 5α-reduced steroids such as 3α17α-dihydroxy-5α-pregnan-20-one, androsterone and 5α-androstane-3α, 17β-diol reached 70%. In contrast to rodents, the immature testes of monkeys and humans do not form large amounts of 5α-reduced C19-steroids. This might reflect a different mechanism controlling testosterone accumulation in the prepubertal testes of monkey and human.
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Presumption
Hydroxyprogesterone
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SUMMARY A variety of 14 C and 3 H-labelled steroids have been perfused through the human adrenal gland in situ and their metabolic products isolated from adrenal venous blood. Progesterone, dehydroepiandrosterone and cortisol were isolated after infusion of [ 3 H]pregnenolone; 17α-hydroxyprogesterone, dehydroepiandrosterone and cortisol after infusion of [ 3 H]17α-hydroxypregnenolone and [ 14 C]progesterone; androstenedione and cortisol after infusion of [ 3 H]17α-hydroxyprogesterone and [ 14 C]dehydroepiandrosterone; and 11β-hydroxyandrostenedione after infusion of [ 3 H]androstenedione and [ 14 C]cortisol. From a consideration of the incorporation of radioactivity into the metabolic products, the 3 H: 14 C ratios and the tissue pool sizes it was concluded that the major biosynthetic pathway to cortisol in the human adrenal glands was: pregnenolone→ 17α-hydroxypregnenolone → cortisol. Progesterone was not an important intermediary. Androstenedione was mainly formed by way of 17α-hydroxypregnenolone → 17α-hydroxyprogesterone → androstenedione. 11β-Hydroxyandrostenedione was formed mainly from cortisol and only a minor amount came from the hydroxylation of androstenedione.
Hydroxyprogesterone
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ABSTRACT Slices of non-luteinized porcine ovaries have been incubated in the presence or absence of human chorionic gonadotrophin (HCG) and exogenous radioactive substrates. Progesterone, 17α-hydroxyprogesterone and androstenedione were isolated in a radiochemically pure form. The chemical mass and the specific activity were determined by gas liquid chromatography and liquid scintillation spectrometry. HCG stimulated the rate of formation of androstenedione in the absence of exogenous substrates with a factor of 4–8. In the presence of pregnenolone or progesterone at a concentration of about 2 × 10− 6 mol/l the stimulatory effect of HCG was either abolished or markedly reduced. The conversion of exogenous progesterone to androstenedione was reduced in response to HCG indicating that the capacity of the tissue to convert progesterone to androstenedione was limited, and that the limit was reached at this rather low substrate concentration. These findings furthermore suggest that the endogenous rather than the exogenous radioactive substrate will be »preferred« by the tissue. The observations demonstrate the necessity of measuring both the radioactivity and the chemical mass of the products in investigations of this type using radioactive substrates. The formation of progesterone from endogenous substrates was also stimulated by HCG. [1- 14 C] acetate and [7α- 3 H]cholesterol were not utilized by the tissue for steroid formation. Exogenous [4- 14 C] pregnenolone and [7α- 3 H] progesterone in similar concentration were both utilized for production of 17α-hydroxyprogesterone and androstenedione. HCG had no effect on the relative utilization of the radioactive substrates.
Hydroxyprogesterone
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The purpose of the present study was to ascertain the relationship between aging and the extent of conversion of plasma androstenedione to estrone. Studies were carried out in 23 women and 26 men who weighed 130–180 pounds and 150–190 pounds, respectively, in which 3H estrone and 14C-androstenedione were administered intravenously and the transfer constant of plasma androstenedione to estrone as measured in urine, [ρ]AE1/BU, was determined. The results of these studies in both women and men demonstrate that with advancing age, there is a progressive and highly statistically significant increase in the efficiency with which circulating androstenedione is converted to estrone. The magnitude of the increase observed in the older subjects reached 2- to 4-fold that observed in the young adult.
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