The metabolism of 19-nor contraceptive progestins modulates their biological activity at the neuroendocrine level

Larrea, Fernando; Vilchis, Felipe; Chávez, Bertha; Pérez, Ana E.; Garza-Flores, J.; Pérez‐Palacios, Gregorio

doi:10.1016/0022-4731(87)90134-8

Cited by 33 publications

(30 citation statements)

References 27 publications

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“…The data confirm and extend the results of previous studies, which have demonstrated the bioconversion of 19-nor synthetic progestins to their A-ring reduced metabolites in other sex steroid hormone sensitive tissues (Larrea et al 1987, Lemus et al 1992). The results are also in line with the presence of androgen metabolizing enzymes reported in bone and bone cells (Vittek et al 1974, Shimodaira et al 1996, Issa et al 2002.…”

Section: Discussionsupporting

confidence: 90%

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Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells

Lemus

Enríquez²,

Hernández³

et al. 2008

Journal of Endocrinology

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A number of clinical studies have demonstrated that norethisterone (NET), a potent synthetic progestin, restores postmenopausal bone loss, although its mode of action on bone cells is not fully understood, while the effect of naturally occurring progesterone in bone has remained controversial. A recent report claims that the potent effects of NET on osteoblastic cell proliferation and differentiation, mimicking the action of estrogens, are mediated by non-phenolic NET derivatives. To determine whether osteoblasts possess the enzymes required to bioconvert a progesterone receptor (PR) agonist into A-ring reduced metabolites with affinity to bind estrogen receptor (ER), we studied the in vitro metabolism of [ 3 H]-labeled NET in cultured neonatal rat osteoblasts and the interaction of its metabolic conversion products with cytosolic -osteoblast ER, employing a competition analysis. Results indicated that NET was extensively bioconverted (36 . 4%) to 5a-reduced metabolites, including 5a-dihydro NET, 3a,5a-tetrahydro NET (3a,5a-NET) and 3b,5a-tetrahydro NET (3b,5a-NET), demonstrating the activities of 5a-steroid reductase and two enzymes of the aldo-keto reductases family. Expression of Srd5a1 in neonatal osteoblast was well demonstrated, whereas Srd5a2 expression was not detected. The most striking finding was that 3b,5a-NET and 3a,5a-NET were efficient competitors of [ 3 H]-estradiol for osteoblast ER binding sites, exhibiting affinities similar to that of estradiol. The results support the concept that the interplay of 5a-steroid reductase and aldo-keto reductases in osteoblastic cells, acting as an intracrine modulator system is capable to bioconvert a PR agonist into ER agonists, offering an explanation of the molecular mechanisms NET uses to enhance osteoblastic cell activities.

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Section: Discussionsupporting

confidence: 90%

“…Previous studies from our laboratory have demonstrated that synthetic 19-nor progestins are extensively metabolized in target organs to A-ring reduced tetrahydro derivatives (Larrea et al 1987, Lemus et al 1992), which exert estrogen-like effects (Vilchis et al 1986, Moralí et al 1990, Lemus et al 2000.…”

Section: Introductionmentioning

confidence: 99%

Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells

Lemus

Enríquez²,

Hernández³

et al. 2008

Journal of Endocrinology

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“…The 3β,5α-reduced metabolite of this compound is able to (Larrea et al 2001, Santillán et al 2001, Pasapera et al 2002, Enríquez et al 2007). This finding is in accordance with further results, showing that tamoxifen (i.e., an estrogen binding site competitor) reduced the effect of 3β,5α-NET administration, and that the activity of 5α-NET is inhibited by the treatment with CPA, a 3β-hydroxysteroid dehydrogenase/Δ4,5 isomerase inhibitor (Larrea et al 1987). The 17-hydroxyprogesterone derivative CMA, together with MPA, is one of the first PROG derivatives.…”

Section: Metabolism Of Progestinssupporting

confidence: 91%

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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“…An early study conducted in postmenopausal women and castrated patients with complete androgen resistance strongly suggested that the antigonadotropic effect of NET is mediated through the ER, while the effect of medroxy-progesterone acetate (MPA) is mediated through the androgen receptor (Pérez-Palacios et al 1981). Studies from our laboratory have demonstrated that synthetic 19-norprogestins are extensively bioconverted in target organs to A-ring reduced tetrahydro derivatives (Larrea et al 1987, Lemus et al 1992) which exert estrogen-like effects (Vilchis et al 1986, Moralí et al 1990, Santillán et al 2001. Furthermore, recent studies have demonstrated that the protecting neurotoxic effects of progestins are mediated by their 3a-and 3b-tetrahydro reduced metabolites (Ghoumari et al 2003, Rhodes et al 2004, Ciriza et al 2006.…”

Section: Introductionmentioning

confidence: 99%

The effects of synthetic 19-norprogestins on osteoblastic cell function are mediated by their non-phenolic reduced metabolites

Enríquez¹,

Lemus²,

Chimal‐Monroy³

et al. 2007

Journal of Endocrinology

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The key role of estrogens on osteoblastic cell function is well documented; however, the role of progesterone (P) and synthetic progestins remains controversial. While several reports indicate that P has no significant effects on bone cells, a number of clinical studies have shown that 19-norprogestins restore postmenopausal bone loss. The mechanisms by which 19-norprogestins induce estrogenlike effects on bone cells are not fully understood. To assess whether the actions of 19-norprogestins on osteoblasts are mediated by their non-phenolic metabolites, we studied the effects of norethisterone (NET), levonorgestrel (LNG), and two of their A-ring reduced derivatives upon cell proliferation and differentiation in neonatal rat osteoblasts. Osteoblast function was assessed by determining cell DNA, cellassociated osteocalcin and calcium content, alkaline phosphatase activity, and mineral deposition. P failed to induce changes on osteoblasts, while NET and LNG exerted a number of actions. The most striking finding was that the 3b,5a-and 3a,5a-tetrahydro derivatives of NET and LNG induced osteoblast proliferation and differentiation with higher potency than those exerted by their parent compounds, mimicking the effects of estradiol. Interestingly, osteoblast differentiation and mineral deposition induced by NET and LNG were abolished by finasteride, a 5a-reductases inhibitor, while the potent effect on osteoblast proliferation induced by progestin derivatives was abolished by a steroidal antiestrogen. Results demonstrate that A-ring reduced derivatives of NET and LNG exhibit intrinsic estrogen-like potency on rat osteoblasts, offering a plausible explanation for the mechanism of action of 19-norprogestins in bone restoration in postmenopausal women and providing new insights for hormone replacement therapy research.

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The metabolism of 19-nor contraceptive progestins modulates their biological activity at the neuroendocrine level

Cited by 33 publications

References 27 publications

Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells

Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells

The other side of progestins: effects in the brain

The effects of synthetic 19-norprogestins on osteoblastic cell function are mediated by their non-phenolic reduced metabolites

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