In Vitro Conversion of Estradiol-17β into Estrone in Normal Human Myometrium und Leiomyoma

Abstract

Summary:The specific activity of 170-hydroxysteroid dehydrogenase was measured in normal human myometrium, and in leiomyoma specimens obtained from the same tumor-bearing uterus. In all cases the normal tissue showed greater conversion of estradiol-17/3 into estrone than the neoplastic tissues. In normal myometrium of fertile women, the specific enzyme activity depended on the phase of the menstrual cycle, the highest values of 170-hydroxysteroid dehydrogenase activity being found in the early secretory phase.To determine the intracellular distribution of the 17/3-hydroxysteroid dehydrogenase, purified microsomes, mitochondria, nuclei and cytosol fractions were prepared. The purity of each fraction was monitored by marker enzymes. It was found that the enzyme was mainly located in mitochondria and microsomes. Furthermore it was demonstrated that the microsomal enzyme was bound tightly to the membranes of the endoplasmic reticulum, while the mitochondrial 17j34iydroxysteroid dehydrogenase was mainly associated with the outer membranes of the organelle.Kinetic parameters (K m -values, coenzyme requirements, temperature and pH-optima) of the cytoplasmic, nuclear, mitochondrial and microsomal enzyme of normal and neoplastic tissue were compared. In vitrO'Umwandlung von Östradiol-17ß in Östron in normalem Human-Myometrium und LeiomyomenZusammenfassung: Die spezifische Aktivität der 17|8-Hydroxysteroiddehydrogenase wurde in normalem HumanMyometrium und in Gewebeproben von Leiomyomen vergleichend gemessen. Die Gewebsproben wurden aus dem gleichen Tumor-tragenden Uterus gewonnen. Normalgewebe zeigte einen größeren Umsatz von Östradiol-170 zu Östron als Tumorgewebe. In Normal-Myometrium geschlechtsreifer Frauen variierte die spezifische Enzymaktivität in Abhängigkeit vom Menstruationszyklus: die höchsten Werte wurden in der frühen Sekretionsphase beobachtet.Um die intrazellulare Verteilung der 17|8-Hydroxysteroiddehydrogenase-Aktivität zu untersuchen, wurden hochgereinigte Mikrosomen, Mitochpndrien, Kerne und Cytoplasma präpariert. Der Reinheitsgrad der Fraktion wurde durch Leitenzyme charakterisiert. Die höchsten spezifischen Enzymaktivitäten wurden in Mitochondrien und Mikrosomen lokalisiert. Darüberhinaus wurde beobachtet, daß das mikrosomale Enzym fest mit der Membran des endoplasmatischen Retikulums verbunden ist, während die mitochondriale 17j3-Hydroxysteroiddehydrogenase mit der äußeren Membran der Mitochondrien assoziiert ist.Kinetische Parameter (K m -Werte, Coenzym-Abhängigkeit, Temperatur-und pH-Optima) des cytoplasmatischen, nuklearen, mitochondrialen und mikrosonialen Enzyms aus normalem und neoplastischem Gewebe wurden vergleichend untersucht.

Glycogen Metabolism of Normal Human Myometrium and Leiomyoma – Possible Hormonal Control

“…The findings of Pollowe t al. [6,7] which point to high local levels of estrogens in the myoma are in accord with a stimulatory role of estrogen as a factor contributing to the increased glycogen levels in metabolically active myomas.…”

“…Nevertheless, it is difficult to understand why normal uterine muscle and myomas would react differently to the same hormonal environment. A possible explana tion was suggested by Pollow et al [6] who found that the activity of (3-hydroxysteroid dehydrogenase, which converts 17 p-estradiol to estrone, a much less potent estrogen, is lower in myomas than in surrounding muscle. These authors also found a higher estradiol-binding capacity and a lower concentration of progesterone receptors in myoma, as compared to normal myometrium [7], These findings could well explain increased estrogen effect on myomas even when the prevailing hormonal environment is low in estrogens.…”

Etiology and pathogenesis of uterine leiomyomas: a review.

“…Because estradiol up-regulates both of these receptors, the increased concentration of estradiol in these tumors compared with that in the myometrium (Otubu et al 1982) could be indicative of a pathogenetic link to the development of leiomyomata. The demonstration of reduced activity in leiomyomas of the enzyme 17β-hydroxysteroid dehydrogenase (Eiletz et al 1980;Pollow et al 1978b), the enzyme responsible for the conversion of estradiol to estrone, would seem to provide a plausible explanation for the accumulation of estradiol in these tumors (Otubu et al 1982). Although estrone is weakly estrogenic, it exhibits a lower binding affinity for ERs than estradiol, and it diffuses out of the cell more rapidly than estradiol.…”

Decreased Induced Retention of the Progesterone Receptor in the Nuclear Extract in Human Uterine Leiomyoma in vivo

“…(2) The activ ity of 17(3-hydroxysteroid dehydrogenase in the LM is decreased [28]; this progesteroneinduced enzyme accelerates the conversion of estradiol to estrone, i.e. to a less active metab olite [29,30].…”