Mechanism of action of levonorgestrel: In vitro metabolism and specific interactions with steroid receptors in target organs

Lemus, Ana E.; Vilchis, Felipe; Damsky, Rebeca; Chávez, Bertha; Garcı́a, Gustavo; Grillasca, Ivonne; Pérez‐Palacios, Gregorio

doi:10.1016/0960-0760(92)90442-l

Cited by 55 publications

(40 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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: 81%

See 1 more Smart Citation

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

Lemus

Enríquez²,

Hernández³

et al. 2008

Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 81%

“…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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Exogenous progestin can directly inhibit steroidogenesis [33]. LNG is a synthetic progestin which has strong progesterone-like and anti-ovulatory activities, but it lacks estrogen-like activity [15]. The profound reduction of serum E2 and P4 levels, despite elevated serum FSH and LH levels in the present study, suggests that the ovary of the Mongolian gerbil may be an important site of action for the direct progesterone-like effects of LNG.…”

Section: Discussionmentioning

confidence: 41%

Effects of Levonorgestrel on Reproductive Hormone Levels and Their Receptor Expression in Mongolian Gerbils (Meriones unguiculatus)

Shi

2011

Exp. Anim.

View full text Add to dashboard Cite

Abstract:The effects of levonorgestrel (LNG) on serum levels of reproductive hormones and their receptor mRNA expression in the ovary and uterus of Mongolian gerbils were examined. The results show that serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increased, whereas serum estradiol (E2) and progesterone (P4) decreased profoundly after LNG treatment. LNG down-regulated the mRNA expression of folliclestimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), estrogen receptor (ER) β and progesterone receptor (PR) in the ovary, and ERα and PR in the uterus of Mongolian gerbils. The down-regulated effects were time-dependent and dose-dependent. LNG had no obvious effects on ERα mRNA expression in the ovary. The findings suggest that LNG impairs reproductive hormone receptor expression at the molecular level in Mongolian gerbils. Also, the two ER subtypes may play different roles in the ovary, and ERβ may not be the predominant ER subtype in the uterus of Mongolian gerbils. The ovary and uterus may be the important sites of action of LNG through its direct progesterone-like effects in Mongolian gerbils.

show abstract

“…Authentic were kindly provided by Schering Mexicana, SA de CV (Mexico City, Mexico) and Schering AG (Berlin, Germany) respectively. Synthesis of the 3b,5a-tetrahydro derivatives of NETand LNG (3b,3b,) and their 3a isomers (3a,5a-NET, (17a-ethynyl-19-Nor-5a-androstan-3a,17b-diol); 3a,5a-LNG, (17a-ethynyl-18-methyl-19-Nor-5a-androstan3a,17b-diol)) was done in our laboratories and their physical and spectroscopic constants have been previously described (Chávez et al 1985, Lemus et al 1992. Finasteride was provided by Merck Sharp and Dhome de Mexico, SA de CV, while the antiestrogen ICI 182 780 was generously supplied by Zeneca Farma (Mexico City, Mexico).…”

Section: Methodsmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

Mechanism of action of levonorgestrel: In vitro metabolism and specific interactions with steroid receptors in target organs

Cited by 55 publications

References 26 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

Effects of Levonorgestrel on Reproductive Hormone Levels and Their Receptor Expression in Mongolian Gerbils (Meriones unguiculatus)

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

Contact Info

Product

Resources

About