Inhibition of Hypothalamic Aromatase Activity by 5 Beta‐Dihydrotestosterone

Schumacher, Michaël; Hutchison, R. E.; Hutchison, J.B.

doi:10.1111/j.1365-2826.1991.tb00266.x

Cited by 13 publications

(10 citation statements)

References 30 publications

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“…It has been proposed that 5␤-reduction of steroids may correspond to an inactivation pathway, thus regulating the amount of substrate available for the formation of biologically active metabolites Steimer and Hutchison, 1981). In addition, 5␤-reduced metabolites of testosterone may directly inhibit the activity of enzymes, such as the aromatase, involved in the formation of neuroactive steroids (Schumacher et al, 1991).…”

Section: Steroids In the Aging Nervous System: The Endocrine Glands Amentioning

confidence: 99%

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Schumacher

Weill-Engerer

Lière

et al. 2003

Progress in Neurobiology

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272

171

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Without medical progress, dementing diseases such as Alzheimer's disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer's disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer's patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer's disease, the phosphorylated tau protein and the ␤-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to 5-androstene-3␤,17␤-diol and to 7␣-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer's patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of ␤-amyloid deposits.

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Section: Steroids In the Aging Nervous System: The Endocrine Glands Amentioning

confidence: 99%

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Schumacher

Weill-Engerer

Lière

et al. 2003

Progress in Neurobiology

Self Cite

272

171

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“…These transformations produce active metabolites, which bind with high affinity to either estrogen or androgen receptors, thereby regulating cellular gene expression (3)(4)(5). By contrast, 5j-reduction is considered to be an inactivation pathway since T is converted into 5P-DHT, a compound that does not bind to steroid receptors and is generally considered to be biologically inert (6, 7 although see 8).…”

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confidence: 99%

“…5P-reductase is present in large amounts in the avian brain (2,7,9), especially during early development (10)(11)(12). Because of this abundance, 5/3-reductase might protect the developing brain from the actions of circulating androgens (8,10). Two mechanisms have been proposed to account for this protective capability.…”

mentioning

confidence: 99%

“…First, if 5j-reductase is co-localized with aromatase or 5a-reductase in steroid-responsive cells, 5j-reduction might reduce the intracellular concentration of substrate available for the synthesis of active metabolites (6). Second, it is possible that 5j-reduced metabolites might directly inhibit aromatization (8). These ideas have been difficult to evaluate, since 5p-reductase is generally measured in brain homogenates or cellular subfractions in which cellular components have been artificially mixed (although see 8,13).…”

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confidence: 99%

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5β‐Reductase and other Androgen‐Metabolizing Enzymes in Primary Cultures of Developing Zebra Finch Telencephalon

Schlinger¹,

Amur‐Umarjee²,

Campagnoni³

et al. 1995

J Neuroendocrinology

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Enzymes in the avian brain irreversibly catalyze the conversion of androgens into either active metabolites (aromatase and 5 alpha-reductase) or inactive metabolites (5 beta-reductase), 5 beta-reductase is thought to influence the formation of active metabolites by reducing the concentration of androgenic substrate available for these reactions. However, because these enzymes have different regional, cellular and subcellular distributions in brain, the traditional method to measure enzyme activity in brain homogenates may be inaccurate because of artificial mixing of enzymes. Recently, we have prepared primary cell cultures from the telencephalons of developing zebra finches. Cell cultures offer the advantage that enzyme activity can be measured in live cells in which the relative distribution of enzymes may more closely reflect that found in vivo. We have previously reported that aromatase is expressed at high levels in these cultures, and that it is active in both neurons and in glia. Here we report on the activities of 5 alpha- and 5 beta-reductase in these cell cultures. Along with aromatase, 5 beta-reductase was expressed at high levels in these mixed cell cultures, including cultures highly enriched in glia. This suggests that 5 beta-reductase is present in non-neuronal cells in brain, possibly co-localized with aromatase. However, despite the presence of 5 beta-reductase, aromatase was detected reliably in vitro even when the concentration of substrate was low. Thus, 5 beta-reductase does not prevent the synthesis of estrogen in the telencephalon of developing zebra finches. By contrast, 5 alpha-reductase activity was very low or absent in these cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The major 5ß-reduction product, 5ß-DHT, inhibits preop¬ tic aromatase activity in the male dove (Schumacher, Hutchison & Hutchison, 1991) and appears to have a regulatory role in oestrogen formation. Our results show that the metabolic profile of a-and ß-reduced metabolites derived from testosterone in the female dove is similar to that of the male ).…”

Section: Discussionmentioning

confidence: 99%

Regulation of female brain aromatase activity during the reproductive cycle of the dove

Hutchison¹,

Wozniak²,

Hutchison³

1992

Journal of Endocrinology

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Oestrogen is formed in the female dove brain. The aim of this study was to determine whether (a) the catalytic properties of the brain aromatase are similar to the ovarian enzyme and (b) aromatase activity in the female brain changes during the reproductive cycle and is influenced by steroids and environmental stimuli. The results show that female preoptic aromatase has a higher substrate affinity than the enzyme in ovarian follicles (apparent Km: preoptic area, 7 nmol/l; ovarian follicles, 29 nmol/l), but a lower activity in the preoptic area (Vmax: preoptic area, 290 fmol/mg tissue per h; ovarian follicles, 843 fmol/mg tissue per h). In intact females with developing follicles, oestradiol-17 beta formation was higher in the posterior hypothalamus than the preoptic area. Females in a later stage of reproductive development (yolked follicles) had a different distribution of oestrogen formation with increased aromatase activity in the preoptic area. Preoptic and posterior hypothalamic aromatase activity of females paired with males for 10 days was positively correlated (r = 0.84, P = 0.0001; r = 0.75, P = 0.001 respectively) with ovarian development. Females with undeveloped ovaries which interacted with males had higher preoptic aromatase activity than visually isolated females with similar ovarian development, suggesting that behavioural stimuli have direct effects on brain aromatase activity which are independent of the ovary. Oestradiol benzoate treatment increased preoptic and posterior hypothalamic aromatase activity in intact and ovariectomized females, and testosterone propionate treatment increased anterior hypothalamic aromatase activity, but did not affect other areas, indicating that the distribution of induced aromatase activity is steroid-specific. Oestrogen treatment in ovariectomized or intact females did not replicate the maximal hypothalamic aromatase activity seen when the ovary contained yolked follicles. We conclude that brain aromatase activity is related directly to ovarian condition during the reproductive cycle of the female dove. As in the male, steroids have a role in the regulation of oestrogen formation in the female hypothalamus; behavioural stimuli are also likely to be involved in the control of the brain enzyme.

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Inhibition of Hypothalamic Aromatase Activity by 5 Beta‐Dihydrotestosterone

Cited by 13 publications

References 30 publications

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

5β‐Reductase and other Androgen‐Metabolizing Enzymes in Primary Cultures of Developing Zebra Finch Telencephalon

Regulation of female brain aromatase activity during the reproductive cycle of the dove

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