The 5α-reductase isoenzymes in the central nervous system

Abstracts of the ISGSH Meeting THE 5a-REDUCTASE ISOENZYMES IN THE CENTRAL NERVOUS SYSTEM A. Poletti. Istituto di Endocrinologia, Milan, Italy The 5c~-reductase (5~x-R) activates several 3keto-D4 steroids to more potent derivatives that may also acquire new biological actions. In males, testosterone (T) is the main substrate and gives rise to the most potent natural androgen, dihydrotestosterone (DHT). In females, progesterone is reduced to dihydroprogesterone, a precursor of tetrahydroprogesterone a natural anxiolytic/anesthetic steroid. Other possible substrates are some gluco- and mineralo-corticoids. Two isoforms of the 5~-R, with limited degree of homology, different biochemical properties, and tissue distribution have been cloned: 5c~-R type 1 and type 2. The two recombinant isoforms expressed in yeast are differentially localized within the cells, possibly reflecting different physiological roles. In androgen-dependent structures, DHT is almost exclusively formed by the 5c~-R type 2. The 5c~-R type 1 (widely distributed in the body, with the highest levels in liver) might be involved in steroid catabolism. In the brain, the role of the two isoenzymes is unknown. By evaluating the gene expression of the two 5c~-Rs in the whole rat brain, we have found that the type l isoform is constantly expressed throughout life, whereas the 5~-R type 2 is expressed at high levels only in the perinatal period. The exposure in utero to the antiandrogen flutamide counteracts the increased expression of the type 2 gene at time of birth only in male rat brain. In adulthood, the type 2 gene is expressed at a low level in particular brain structures like the hypothalamus and the hippocampus and at high levels in the spinal cord. Among the various brain cell populations, both the glial and the neuronal cells express the type l gene; the 5c~-R type 2 gene is expressed normally in neuronal hippocampal cells, whereas it becomes detectable in neuronal hypothalamic cells only after induction with T or TPA. Finally, a particular type of hypothalamic neurons (the GTI-1 cells, which originate from the LHRH-producing system and secrete the hypothalamic hormone), expresses both 5c~-R isoforms, but apparently only the 5~x-R type 2 is efficiently translated into a protein. The colocalization of 5c~-R type 2 and of the androgen receptor in GTI-l cells suggests that these neurons are potential androgen-target structures. The physiological significance of the data summarized will be discussed. Grants funding ACRO95,00395.PF39, CNR CT96.03105.CT04. Aging95.00470PF40. FATMA95.00868PF41 is grate.fully acknowledged.

SEX STEROIDS CONCENTRATION IN FATTY TISSUE AFTER MENOPAUSE A. Milewicz. Department of Endocrinology, Medical University, Wroclaw, Poland Adipose tissue plays an important role in the metabolism of sex steroids, especially in women. To examine whether the tissue level of sex steroids varies in obesity and in different regions of the body, their concentration was assessed in adipose tissue from the abdominal integuments in 10 obese and 8 nonobese postmenopausal women and also in subcutaneous adipose tissue from the breast and abdominal integuments and omentum in 6 postmenopausal women. The levels of androstanedione, androstenediol, testosterone (T), dehydroepiandrosterone, estrone (El), estradiol, estrone and estradiol sulphate were measured by means of a previously described method (Steroids 50:297,1987). Obese women displayed an increased (p < 0.05) level of T (1006.8 +_ 501.5) versus nonobese women (587.7 +__221.4 fmol/g); the levels of the remaining steroids did not differ. The correlation of E I (p < 0.001) and androstanedione (p < 0.02) with BMI was found to be more pronounced in obese subjects. Estrone concentration in fatty tissue from breast was significantly lower (979.0 +_ 424.0) versus abdominal and omentum fatty tissue (1370.0 _ 441.5; 1141.8 +_ 350.0 pmol/g), but the levels of the remaining steroids did not differ. The results of the study can indicate the influence of sex steroids on fatty tissue distribution in postmenopausal women.

Steroids, 1997, vol. 62, November

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