David K. Fukushima

THE EFFECTS OF THYROID HORMONES ON THE METABOLISM OF STEROIDS

This study is concerned with observations on the influence of thyroid hormones on the peripheral transformation of steroids in human subjects. The interrelation of these hormones was suggested by the fact that patients with untreated myxedema exhibited an extreme diminution in androsterone formation when compared with normal subjects. Furthermore, it was found that triiodothyronine could increase the production of androsterone in euthyroid subjects as well as in patients with myxedema.’ The studies to be described fall into three groups: (1) the definition of the quantity and kind of endogenous androgen metabolites in myxedematous, euthyroid, and hyperthyroid subjects; (2) the effect of deficiency or excess of thyroid hormone on the metabolism of exogenous androgen; and ( 3 ) investigation of the “thyromimetic” effect of androsterone. The steroid hormone metabolites that have been examined in this study are shown in FIGURE 1. Both of the compounds formulated, androsterone and etiocholanolone, are major end-products of androgen metabolism in man. They are structurally identical except for the orientation of the hydrogen atom attached to C-5, which is a in androsterone and /3 in etiocholanolone. This might seem to be a minor chemical difference; it actually represents a very significant change in the shape of the molecule. Because of this structural dissimilarity each compound has a profoundly different biological activity. Three major potential precursors of these metabolites are also shown in FIGURE 1, and it should be emphasized that these hormones are secreted both by the adrenal gland and by the testes. In this presentation we are concerned primarily with the quantitative relationship between these two products of androgen metabolism. In order to clarify this relationship we have employed the term androsterone fraction. This value represents the percentage of the total amount of androsterone plus etiocholanolone that is comprised by androsterone alone. The effect of hypothyroidism on androgen metabolism is shown in FIGURE 2. We have compared a group of control subjects matched, in so far as possible, as to age and sex with a group of patients with myxedema. We have studied the endogenous production of these metabolites from their precursors in each group by chromatographic methods that have been well standardized and used for many years in our lab0ratories.2.~ We have studied similarly both groups of patients with respect to their ability to metabolize a tracer dose of parenterally administered testosterone-4-C14. For this purpose the radioactive hormone was administered intravenously, and complete urine collections were

Chemistry of 3α-hydroxy-Δ5-androstene-17-one

The synthesis and reactions of 3α-hydroxy-Δ5-androstene-17-one are described. The preparation of 3β-hydroxy-Δ5-androstene-17-one-3α-H3 and its epimer, 3α-hydroxy-Δ5-androstene-17-one-3β-H3, is also reported.

The synthesis of 3β,11β,17,21-tetrahydroxy-Δ5-pregnene-20-one and its 11-keto analog

3β,11β,17,21-Tetrahydroxy-Δ5-pregnene-20-one and its 11-keto analog have been synthesized from hydrocortisone-BMD. Sodium bismuthate oxidation of the unsaturated tetrolone yielded 3β,11β-dihydroxy-5,6α-oxidoandrostane-17-one as well as the expected 3β,11β-dihydroxy-Δ5-androstene-17-one. The 5α,6α-oxide was identical with the major product from the monoperphthalic acid oxidation of 3β,11β-dihydroxy-Δ5-androstene-17-one.

Sterol and Steroid Metabolism

Publisher Summary This chapter discusses the metabolism of cholesterol, adrenocortical hormones, androgens, progesterone, and estrogens. The biosynthesis of cholesterol is most complex and has challenged the ingenuity of investigators for many years. With the availability of isotopes, however, some indication of the pathway by which this molecule is synthesized has been revealed. The direct precursors of cholesterol are relatively simple molecules. The knowledge of the metabolism of androgens has been derived principally from the studies of the isolation of these steroids from tissues and urine, the characterization of urinary excretion products after administration of 19-carbon steroids, and in vitro studies with tissues. The use of isotopically labeled steroids affords more direct evidence for their metabolism, but as yet, the reports in the literature on tracer studies with 19-carbon steroids have been meager. No information dealing with the biosynthesis of progesterone from smaller molecules is available. However, in a study described in the chapter, when deuterium-labeled cholesterol was fed to a woman in the eighth month of pregnancy, isotopically labeled pregnane-3α, 20α- diol, a recognized metabolite of progesterone, was obtained from the urine. When the isotopic content of the urinary pregnanediol was related to that of blood cholesterol, it was calculated that at least 68% of the diol was derived from cholesterol.

Metabolism of adrenosterone

Abstract The metabolism of simultaneously administered adrenosterone-1,2-3H and 11β-hydroxy-Δ4-androstene-3,17-dione-4-14C has been studied in a normal and a hypothyroid subject. Conversion to the metabolites from either hormone was essentially alike demonstrating ready interconversion of the 11β-hydroxy and 11-keto groups of the administered hormones. Following a large dose of adrenosterone to a hypothyroid subject 3α-hydroxy-Δ4-and-rostene-11, 17-dione and its reaction product with urea, 3α-ureido-Δ4-and-rostene-11, 17-dione were isolated and characterized.

Studies on 3α-hydroxy-5α-pregnan-20-one-4-14C.

Abstract The transformation of 3α-hydroxy-5α-pregnan-20-one-4-14 C has been studied in two subjects. Only about one-third of the dose was excreted in the urine during 4 days following administration of the steroid. Considerable amounts of radioactivity, 16.4 and 29% of dose, were excreted by the fecal roote. The total identifiable urinary metabolites were very low, 7.5–10%, with 5α-pregnane-3α,20α-diol the major metabolite. The only other compound isolated was the injected steroid. The further transformation of the 5α-metabolites of progesterone may play a role in the metabolism of progesterone leading to low recovery of metabolites of this hormone.