Therapeutic implications of brain steroidogenesis

The nervous system is a steroidogenic tissue and several steroids synthesized locally in the brain, such as pregnenolone, progesterone and estradiol, modulate neuronal and glial physiology and are neuroprotective. The brain upregulates steroidogenesis at sites of injury as part of a program triggered by neural tissue to cope with neurodegenerative insults. Pharmacological targets to increase brain steroidogenesis and promote neuroprotection include the molecules that transport cholesterol to the inner mitochondrial membrane, where the first enzyme for steroidogenesis is located. Furthermore, the human gene encoding aromatase, the enzyme that synthesizes estradiol, is under the control of different tissue-specific promoters, and it is therefore conceivable that selective aromatase modulators can be developed that will enhance the expression of the enzyme and the consequent increase in estrogen formation in the brain but not in other tissues.

Stimulation of pregnenolone metabolism and aromatase activity by luteinizing hormone in mouse uterus

In vitro metabolism of pregnenolone (P5) as well as production of 17beta-estradiol (E2) were studied in uteri of untreated and luteinizing hormone (LH)-treated mice that had been ovariectomized (OVX) at late-diestrus stage. In the uteri of untreated mice, [H]pregnenolone was shown to be metabolized to Delta-components such as 17alpha-hydroxypregnenolone (17alpha-P5) and dehydroepiandrosterone (DHEA), whereas LH treatment resulted in significant increases in the formation of progesterone (P4), 17alpha-hydroxyprogesterone (17alpha-P4), androstenedione (AD) and testosterone (T). This was assessed by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). The content and release of P4 was shown to be stimulated by LH. Trilostane, an inhibitor of 3beta-hydroxysteroid dehydrogenase (3beta-HSD), inhibited LH-induced P4 synthesis and its release in a dose-dependent manner. A considerable increase in [H]estradiol formation from [H]testosterone was recorded in LH-stimulated uterine tissue as compared with the control, indicating the stimulatory effect of LH on aromatase activity. LH-stimulation in the synthesis of P4 and E2 in OVX mouse uteri was mimicked by dbcAMP (cell-permeable cAMP). Incubation with LH was shown to augment the conversion of P4 to various delta-3-oxosteroids. In vitro effects of LH on the synthesis and metabolism of P4, as well as on the stimulation of aromatase activity, were more pronounced in the uterine tissue of LH-primed OVX mice. Thus the results of the present study indicate that, under specific conditions, the uterus of the mouse behaves like steroidogenic tissue. Its prompt response to LH reveals the probable physiological relevance of the existence of LH receptors of high binding affinity in the uterine tissue of the mouse, as reported earlier.