Effects of norethisterone on bone related biochemical variables and forearm bone mineral in post‐menopausal osteoporosis

Horowitz, Michael; Wishart, Judith M.; Need, A. G.; Morris, H. A.; Nordin, B. E. C.

doi:10.1111/j.1365-2265.1993.tb02422.x

Cited by 55 publications

(21 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The progestogen norethisterone has androgenic/ anabolic properties and there is evidence that a small proportion of norethisterone is metabolized to ethinyl estradiol [4]. Norethisterone given in a dose of 5-10 mg daily lowers urinary calcium and hydroxyproline, and inhibits bone resorption [5][6][7][8]. As with estrogen therapy, this inhibition of bone resorption is associated with retardation of postmenopausal bone loss [5,8,9].…”

Section: Introductionmentioning

confidence: 99%

The Effects of Low Dose Norethisterone on Biochemical Variables in Postmenopausal Women

Scopacasa

Horowitz

Need

et al. 1999

Osteoporosis International

View full text Add to dashboard Cite

Norethisterone 2.5 mg/day was administered to 26 postmenopausal women (aged 54-79 years) with varying degrees of osteoporosis and with a forearm bone mineral density value more than 2 SD below the young normal mean. Fasting blood and urine samples were collected and radiocalcium absorption measured at baseline and after treatment for a median period of 4 months. There were significant falls in serum calcium and its fractions, phosphate, alkaline phosphatase and cholesterol (HDL and LDL), and significant rises in serum chloride and parathyroid hormone. In the urine, there were significant falls in calcium, sodium and hydroxyproline. These changes were in close agreement with our previously reported responses to norethisterone 5 mg/day. We conclude that norethisterone in a dose of 2.5 mg/day is probably as effective as 5 mg/day in reducing bone resorption in postmenopausal women with low bone density.

show abstract

Section: Introductionmentioning

confidence: 99%

The Effects of Low Dose Norethisterone on Biochemical Variables in Postmenopausal Women

Scopacasa

Horowitz

Need

et al. 1999

Osteoporosis International

View full text Add to dashboard Cite

show abstract

“…In contrast, administration of 19-norprogestins induces beneficial effects on bone turnover. Indeed, a number of clinical studies (Abdalla et al 1985, Christiansen & Riis 1990, Horowitz et al 1993 have shown that administration of norethisterone (NET), a synthetic 19-norprogestin, prevents bone mineral loss and reduces bone resorption in postmenopausal women, and also prevents bone loss in young women treated with luteinizing hormonereleasing hormone agonists (Riis et al 1990). In addition, low-dose subdermal administration of levonorgestrel (LNG), another synthetic 19-norprogestin, also induces an increase in bone mineral density in premenopausal women (Di et al 1999).…”

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

“…A number of clinical trials have demonstrated that administration of norethisterone (NET), a synthetic 19-nor progestin, to postmenopausal women prevents bone mineral loss and reduces bone resorption (Abdalla et al 1985, Horowitz et al 1993 and also prevents bone loss in young women treated with LH-releasing agonists (Riis et al 1990). The mechanisms of estrogen-like bone actions of NET are not fully understood, particularly since this steroid molecule neither interacts with estrogen receptors (ER; Chávez et al 1985) nor undergoes enzyme-mediated aromatization (Gual et al 1962).…”

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

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

Effects of norethisterone on bone related biochemical variables and forearm bone mineral in post‐menopausal osteoporosis

Abstract: These results suggest that norethisterone prevents bone loss in post-menopausal osteoporosis by decreasing bone turnover, has a vitamin-D independent effect on intestinal calcium absorption, and increases serum parathyroid hormone levels.

Cited by 55 publications

References 37 publications

The Effects of Low Dose Norethisterone on Biochemical Variables in Postmenopausal Women

The Effects of Low Dose Norethisterone on Biochemical Variables in Postmenopausal Women

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

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

Contact Info

Product

Resources

About