Selectivity and potency of the retroprogesterone dydrogesterone in vitro

Rižner, Tea Lanišnik; Brožič, Petra; Doucette, Christopher; Turek-Etienne, Tammy C.; Müller‐Vieira, Ursula; Sonneveld, Edwin; Burg, Bart van der; Böcker, Christiane; Husen, Bettina

doi:10.1016/j.steroids.2011.02.043

Cited by 73 publications

(63 citation statements)

References 34 publications

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“…The progestin dydrogesterone is used for hormone-replacement therapy, for treatment of endometriosis, menstrual disorders, corpus luteum insufficiency and habitual or threatened abortions [46]. Dydrogesterone is metabolized to the active 20α-hydroxy-metabolite, 20α-hydroxy-9β,10α-pregna-4,6-diene-3-one by AKR1C1 and AKR1C2 enzymes and acts as μM inhibitor of AKR1C3 [11, 13].…”

Section: Human Akr1 Enzymes Implicated In Steroid Metabolismmentioning

confidence: 99%

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

2014

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Human aldo-keto reductases AKR1C1-AKR1C4 and AKR1D1 play essential roles in the metabolism of all steroid hormones, the biosynthesis of neurosteroids and bile acids, the metabolism of conjugated steroids, and synthetic therapeutic steroids. These enzymes catalyze NADPH dependent reductions at the C3, C5, C17 and C20 positions on the steroid nucleus and side-chain. AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents, while AKR1D1 acts as the sole Δ4-3-ketosteroid-5β-reductase (steroid 5β-reductase) in humans. AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and trans-activation, they also regulate the amount of neurosteroids that can modulate the activity of GABAA and NMDA receptors. As such they are involved in the pre-receptor regulation of nuclear and membrane bound receptors. Altered expression of individual AKR1C genes is related to development of prostate, breast, and endometrial cancer. Mutations in AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency.

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Section: Human Akr1 Enzymes Implicated In Steroid Metabolismmentioning

confidence: 99%

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

2014

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“…This is due to the rigid conformation of its retrostructure, which is suitable for its interaction with PGR, but not with the other steroid hormone receptors (Colombo et al 2006). In particular, dydrogesterone is inactive as agonists of human mineralocorticoid receptor (MR) and shows negligible androgenic, estrogenic or mineralocorticoid activities (Kuhl 2005, Rižner et al 2011.…”

Section: Progestins Structurally Related To Progesteronementioning

confidence: 99%

The other side of progestins: effects in the brain

Giatti

Melcangi

Pesaresi

2016

Journal of Molecular Endocrinology

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Progestins are a broad class of progestational agents widely differing in their chemical structures and pharmacological properties. Despite emerging data suggest that progestins, besides their action as endometrial protection, can also have multiple nonreproductive functions, much remains to be discovered regarding the actions exerted by these molecules in the nervous system. Here, we report the role exerted by different progestins, currently used for contraception or in postmenopausal hormone replacement therapies, in regulating cognitive functions as well as social behavior and mood. We provide evidence that the effects and mechanisms underlying their actions are still confusing due to the use of different estrogens and progestins as well as different doses, duration of exposure, route of administration, baseline hormonal status and age of treated women. We also discuss the emerging issue concerning the relevant increase of these substances in the environment, able to deeply affect aquatic wildlife as well as to exert a possible influence in humans, which may be exposed to these compounds via contaminated drinking water and seafood. Finally, we report literature data showing the neurobiological action of progestins and in particular their importance during neurodegenerative events. This is extremely interesting, since some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system, opening new promising opportunities for the use of these molecules as therapeutic agents for trauma and neurodegenerative disorders.

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“…These data indicated that this steroid showed selectivity for PR type B, and this offers a therapeutical advantage, since each type induces different physiological function in target tissues 4 . However, dydrogesterone did not bind to ER (types a and b), AR or glucocorticoid receptor (GR); and as a result of this, it could prevent collateral effects 51 . The pharmaceutical effect of dydrogesterone has been described as a neuroendocrine's modulator of ovarian and endometrial functions 52 .…”

Section: Current Use Of Progestins For Cancer Treatment Contraceptiomentioning

confidence: 99%

“…The pharmaceutical effect of dydrogesterone has been described as a neuroendocrine's modulator of ovarian and endometrial functions 52 . On the other hand, dydrogesterone inhibited the activity of the enzymes 5a-reductase type 2 (5a-R2) as well as 17-b-hydroxysteroid dehydrogenase (17-b-HSD) types 3 and 5 51 . These data are important since the growth of estrogen/progesterone-insensitive breast cancer tumors is due to the presence of a high concentration of 5a-progesterone (5aP) metabolite 53 .…”

Section: Current Use Of Progestins For Cancer Treatment Contraceptiomentioning

confidence: 99%

Recent advances in structure of progestins and their binding to progesterone receptors

Cabeza

Heuze

Sánchez

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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The role of progesterone in women's cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.

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Selectivity and potency of the retroprogesterone dydrogesterone in vitro

Cited by 73 publications

References 34 publications

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

The other side of progestins: effects in the brain

Recent advances in structure of progestins and their binding to progesterone receptors

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