STUDIES ON THE METABOLISM OF C-19 STEROIDS IN THE HUMAN FOETO-PLACENTAL UNIT

Abstract

ABSTRACT Previable foetuses were perfused with 3H-labelled testosterone (T) plus 14C-labelled androstenedione (A), or with 3H-labelled dehydroepiandrosterone plus 14C-labelled A. In addition, in two experiments half of the liver and one adrenal of foetuses perfused with 3H-labelled A were incubated with 14C-labelled A. From the various tissues several products of aromatisation and hydroxylation were isolated in a radiochemically homogeneous form. Oestrogens were present only in the extracts of livers and in the perfusates. From the livers oestrone, 17β-oestradiol, 15α-hydroxy-oestradiol and oestriol were isolated. Following reduction with KBH4 of the fraction containing 16epi-oestriol together with ring D hydroxy-ketones, 15α-hydroxy-oestradiol, oestriol and 16epi-oestriol were isolated. These oestrogens, which were present exclusively as conjugated material, were only formed from A and T, but not from dehydroepiandrosterone. Conjugated oestrone, but no 17β-oestradiol was isolated from the perfusates. No oestrogens were detected in the extracts of the adrenals, not even following the perfusion and subsequent incubation with large amounts of A. Oestrogens were also absent from the combined extracts of all other foetal tissues. Unconjugated 11β-hydroxy-androstenedione was isolated from the adrenals as the principal metabolite of A both in the perfusion and incubation studies. It was also isolated from the perfusates. Conjugated 11β-hydroxy-testosterone was isolated from the adrenals as a major metabolite of T. No unconjugated 1 1β-hydroxy-testosterone was detected in any of the perfusion or incubation experiments. Little, if any adrenosterone was present in the adrenals. However, this compound was isolated from the extracts of the lungs and residual tissues. No qualitative sex difference was found in the formation of any of the compounds isolated. The formation of 15- and 16-oxygenated oestrogens by the liver was contrasted by the absence of 15α-hydroxy-androstenedione, 15α-hydroxy-testosterone, 16α-hydroxy-androstenedione, or 16α-hydroxy-testosterone from any of the tissues. Lack of 16α-hydroxylation of A was also demonstrated following the incubation of A with homogenates of adrenals and livers. It is concluded that: aromatisation in the foetal organism takes place only in the liver and exclusively from α,β-unsaturated 3-ketosteroids, part of the conjugated oestrogen formed by the foetal liver is released into the foeto-placental circulation, mainly, if not entirely, in a ketonic form, 15α- and 16α-hydroxylation of A and T is preceded by aromatisation and takes place only in the liver, part of the A secreted by the placenta to the foetus is returned to the placenta in the form of 11β-hydroxy-androstenedione.