‘New’ active steroids and an unforeseen mechanism of action

Baulieu, Étienne Émile

doi:10.1016/s0764-4469(00)00169-4

Cited by 6 publications

(6 citation statements)

References 20 publications

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“…Recently, evidence was obtained that intracellular receptors also trigger cascades of molecular assembly (e.g., tubulin polymerization) 28. Thus, for intracellular receptors previously thought to be involved only in gene regulation, rapid mechanisms are beginning to unfold.…”

Section: Brain Corticosteroid Receptors Operate In Binary Fashionmentioning

confidence: 99%

Hormones and the Stressed Brain

Kloet

2004

Annals of the New York Academy of Sciences

258

147

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A BSTRACT : The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system. Their action-in concert-is crucial for individual differences in coping with other individuals, which in turn depend on genetic-and experience-related factors. The actions exerted by cortisol and corticosterone have an enormous diversity. They include the regulation of rapid molecular aggregations, membrane processes, and gene transcription. In the latter transcriptional regulation, the corticosteroid hormones have two modes of operation. One mode is mediated by high-affinity mineralocorticoid receptors (MRs), which control gene networks underlying stabilization of neuronal activity as determinant for the sensitivity to trigger immediate responses to stress organized by corticotrophin-releasing hormone (CRH)-1 receptor. Whereas disturbance of homeostasis is prevented by MR-mediated processes, its recovery is facilitated via the low-affinity glucocorticoid receptors (GRs) that require stress levels of cortisol. GRs promote in coordination with CRH-2 receptors and the parasympathetic system behavioral adaptation and enhances storage of energy and information in preparation for future events. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance, and health. Imbalance induced by genetic modification or stressors changes specific neural signaling pathways underlying cognition and emotion. This yin-yang concept in stress regulation is fundamental for genomic strategies to understand the mechanistic underpinning of corticosteroid-induced stress-related disorders such as severe forms of depression.

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Section: Brain Corticosteroid Receptors Operate In Binary Fashionmentioning

confidence: 99%

Hormones and the Stressed Brain

Kloet

2004

Annals of the New York Academy of Sciences

258

147

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“…They act as modulators of several neurotransmitter receptors (g-aminobutyric acid A , N-methyl-Daspartate, and d1 receptors), either as stimulators or inhibitors, and are involved in learning and memory performance. The biosynthesis of the neurosteroids in glial cells starts with cholesterol, which is first converted to PREG, progesterone, 5a-pregnane-3,20-dione (5aDH-PROG or 5a-DHP) and then to 3a-hydroxy-5a-pregnane-20-one (3a,5a-TH-PROG) or 3a,5a-THP or allopregnanolone 109,110 . 5a-Reductase type II, one of the two 5a-reductase isoforms, is thought to be a key enzyme in the generation of neuroactive steroids in the brain, particularly allopregnanolone.…”

Section: Progesterone and The Central Nervous Systemmentioning

confidence: 99%

“…by increasing the activity of antioxidative catalase or by modifying the microtubuleassociated protein-2 content 109,[121][122][123][124] . In this context, progesterone and allopregnanolone inhibited cell death and cognitive deficits, including recovery of select behaviors after a contusion of the rat pre-frontal cortex 125,126 .…”

Section: Progesterone and The Central Nervous Systemmentioning

confidence: 99%

Progesterone: the forgotten hormone in men?

Oettel¹,

Mukhopadhyay²

2004

The Aging Male

167

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'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in birds and mammals that they are detectable. In the different species, they mediate manifold effects regarding the differentiation of target organ functions, mainly in the reproductive system. Surprisingly, we know little about the physiology, endocrinology, and pharmacology of progesterone and progestins in male gender or men respectively, despite the fact that, as to progesterone secretion and serum progesterone levels, there are no great quantitative differences between men and women (at least outside the luteal phase). In a prospective cohort study of 1026 men with and without cardiovascular disease, we were not able to demonstrate any age-dependent change in serum progesterone concentrations. Progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. Other progesterone effects in men include those on the central nervous system (CNS) (mainly mediated by 5alpha-reduced progesterone metabolites as so-called neurosteroids), including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate weight gain and appetite in men as well as in women. The detection of progesterone receptor isoforms would have a highly diagnostic value in prostate pathology (benign prostatic hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets is connected with a great pharmacodynamic variability. The reason for this is that, in men, some important effects of progesterone are mediated non-genomically through different molecular biological modes of action. Therefore, the precise therapeutic manipulation of progesterone actions in the male requires completely new endocrine-pharmacological approaches.

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“…the oxytocin receptor, is also modulated by pregnane derivatives [86] again demonstrating the complex interplay between peptide and steroid ligands. An additional role of neurosteroids in regulation of tubulin polymerization was recently reported [87]. In summary, steroids locally produced in brain are involved in the control of metabolic, behavioral, and psychical processes including cognition, stress, anxiety and sleep [83,85].…”

Section: Neurosteroidsmentioning

confidence: 99%

Metabolic conversion as a pre‐receptor control mechanism for lipophilic hormones

Nobel

Abrahmsén

Oppermann

2001

European Journal of Biochemistry

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The majority of physiological effects mediated by steroids, retinoids and thyroids is accomplished by binding to members of the nuclear receptor superfamily of ligand activated transcription factors. The complex specific effects of lipid hormones depend not only on receptor expression, distribution and interactions, but also on the availability and metabolic conversion of the hormone itself. The cellspecific metabolic activation of inactive hormone precursors introduces a further level of hormonal regulation, and constitutes an important concept in endocrinology. The metabolic reactions carried out are achieved by dehydrogenases/reductases, hydroxylases and other enzymes, acting on ligands of the steroid/thyroid/retinoic hormone receptor superfamily. The concept implies that these tissue-and cellspecific metabolic conversions contribute to lipid hormone action, thus pointing to novel targets in drug development. All components of this signalling system, the hormone compounds, the receptor proteins, and modifying enzyme families originate from an early metazoan date, emphasizing the essential nature of all elements for development and diversification of vertebrate life.

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‘New’ active steroids and an unforeseen mechanism of action

Cited by 6 publications

References 20 publications

Hormones and the Stressed Brain

Hormones and the Stressed Brain

Progesterone: the forgotten hormone in men?

Metabolic conversion as a pre‐receptor control mechanism for lipophilic hormones

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