Comparative effects of progesterone and the synthetic progestin norethindrone on neuroprotection in a model of spontaneous motoneuron degeneration.

The Wobbler mouse has been proposed as an experimental model of the sporadic form of amyotrophic lateral sclerosis (ALS). The administration of natural progesterone (PROG) to Wobbler mice attenuates neuropathology, inhibits oxidative stress, enhances the expression of genes involved in motoneuron function, increases survival and restores axonal transport. However, current pharmacological treatments for ALS patients are still partially effective. This encouraged us to investigate if the synthetic progestin norethindrone (NOR), showing higher potency than PROG and used for birth control and hormone therapy might also afford neuroprotection. Two-month-old Wobbler mice (wr/wr) were left untreated or received either a 20 mg pellet of PROG or a 1 mg pellet of NOR for 18 days. Untreated control NFR/NFR mice (background strain for Wobbler) were also employed. Wobblers showed typical clinical and spinal cord abnormalities, while these abnormalities were normalized with PROG treatment. Surprisingly, we found that NOR did not increase immunoreactivity and gene expression for choline-acetyltransferase, drastically decreased GFAP + astrogliosis, favored proinflammatory mediators, promoted the inflammatory phenotype of IBA1+ microglia, increased the receptor for advanced glycation end products (RAGE) mRNA and protein expression and the activity of nitric oxide synthase (NOS)/NADPH diaphorase in the cervical spinal cord. Additionally, NOR treatment produced atrophy of the thymus. The combined negative effects of NOR on clinical assessments (forelimb atrophy and rotarod performance) suggest a detrimental effect on muscle trophism and motor function. These findings reinforce the evidence that the type of progestin used for contraception, endometriosis or replacement therapy, may condition the outcome of preclinical and clinical studies targeting neurodegenerative diseases.

Effects of a soy-based dietary supplement compared with low-dose hormone therapy on the urogenital system: a randomized, double-blind, controlled clinical trial.

OBJECTIVE: This study aims to compare the effects of a soy-based dietary supplement, low-dose hormone therapy (HT), and placebo on the urogenital system in postmenopausal women. METHODS: In this double-blind, randomized, placebo-controlled trial, 60 healthy postmenopausal women aged 40 to 60 years (mean time since menopause, 4.1 y) were randomized into three groups: a soy dietary supplement group (90 mg of isoflavone), a low-dose HT group (1 mg of estradiol plus 0.5 mg of norethisterone), and a placebo group. Urinary, vaginal, and sexual complaints were evaluated using the urogenital subscale of the Menopause Rating Scale. Vaginal maturation value was calculated. Transvaginal sonography was performed to evaluate endometrial thickness. Genital bleeding pattern was assessed. Statistical analysis was performed using χ(2) test, Fisher's exact test, paired Student's t test, Kruskal-Wallis test, Kruskal-Wallis nonparametric test, and analysis of variance. For intergroup comparisons, Kruskal-Wallis nonparametric test (followed by Mann-Whitney U test) was used. RESULTS: Vaginal dryness improved significantly in the soy and HT groups (P = 0.04). Urinary and sexual symptoms did not change with treatment in the three groups. After 16 weeks of treatment, there was a significant increase in maturation value only in the HT group (P < 0.01). Vaginal pH decreased only in this group (P < 0.01). There were no statistically significant differences in endometrial thickness between the three groups, and the adverse effects evaluated were similar. CONCLUSIONS: This study shows that a soy-based dietary supplement used for 16 weeks fails to exert estrogenic action on the urogenital tract but improves vaginal dryness.

Estrogen-free oral hormonal contraception: benefits of the progestin-only pill.

Although combined oral contraceptives (COCs) are commonly used and highly effective in preventing pregnancy, they may not be suitable for some women. COC use is associated with increased rates of cardiovascular events and is not recommended in nonbreastfeeding women in the immediate postpartum period or in breastfeeding women during the initial 6 months of breastfeeding. Moreover, estrogen-related adverse effects, such as headache, are common. Estrogen-free progestin-only pills (POPs) are a valuable option in women who prefer to take an oral hormonal contraceptive, but are ineligible for, or choose not to use, COCs. Although some POPs have been associated with lower contraceptive effectiveness than COCs, the POP containing desogestrel has shown similar contraceptive effectiveness to COCs. The most commonly reported complaints in women using all POPs are bleeding problems. Counseling women interested in using POPs about the variable bleeding patterns associated with this method may improve compliance and acceptance.

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

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 5 alpha-reduced metabolites, including 5 alpha-dihydro NET, 3 alpha,5 alpha-tetrahydro NET (3 alpha,5 alpha-NET) and 3beta,5 alpha-tetrahydro NET (3beta,5 alpha-NET), demonstrating the activities of 5 alpha-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 3beta,5 alpha-NET and 3 alpha,5 alpha-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 5 alpha-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.

A possible role of progesterone receptor in mouse oocyte in vitro fertilization regulated by norethisterone and its reduced metabolite.

BACKGROUND: The contraceptive effect of the progestogen norethisterone (NET) and its main metabolites 5alpha-NET and 3beta,5alpha-NET has been demonstrated in several species, and most studies have focused on the effects of these compounds in the uterus. We previously reported that 5alpha-NET inhibits the progesterone (P(4))-induced acrosome reaction in pig and mouse spermatozoa and induces severe morphological damage in two-cell fertilized mouse oocytes. STUDY DESIGN: The main goal of this study was to analyze the possible role of P(4) receptor (PR) in the effects of NET and 5alpha-NET on the oocyte fertilization process. Different steroid treatments were used with or without cumulus-enclosed oocytes. RESULTS: It was demonstrated that NET increases the percentage of fertilized oocytes in the same manner as P(4) does, while 5alpha-NET reduces the percentage of fertilized oocytes. This effect was not reversed by P(4) in the same concentrations. CONCLUSION: A possible molecular mechanism for the effects of 5alpha-NET may be through a PR localized in the oocyte plasma membrane.

Effects of estradiol and norethisterone on lipids, insulin resistance and carotid flow.

OBJECTIVES: To evaluate the lipid profile, insulin resistance and vasomotricity, and the interaction between these factors, in postmenopausal women receiving hormone therapy. METHODS: A prospective, randomized, double-blind study was carried out in which 77 postmenopausal women received one of the three treatment regimens: (A) 2mg oral micronized estradiol (E2) (n=25); (B) 2mg oral E2+1mg oral norethisterone acetate (NETA) (n=28); or C) placebo (n=24), daily for 6 months. Evaluations were carried out at baseline and at the end of treatment on lipid and lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and pulsatility index (PI) of the internal carotid artery by Doppler ultrasonography. RESULTS: Mean increases of 15.6% and 2.4% and a reduction of 6.4% in high-density lipoprotein (HDL) levels were found for the E2, E2+NETA and placebo groups, respectively. Reductions of 9.5% and 3.7% and an increase of 12.1% in low-density lipoprotein (LDL), and reductions of 20.0% and 3.8% and an increase of 28.8% in the LDL:HDL ratio were found for the E2, E2+NETA and placebo groups, respectively (p<0.001 in all cases). Insulin levels and HOMA-IR decreased 12.8% and 12.3% in the E2 group and increased 12.9% and 16.0% in the E2+NETA group (p<0.05), respectively. Carotid PI following treatment was 1.18+/-0.23, 1.38+/-0.20 and 1.41+/-0.21 for the E2, E2+NETA and placebo groups, respectively (p=0.0006). CONCLUSIONS: Oral estrogen therapy led to an improvement in lipid profile, insulin resistance and carotid blood flow, which was cancelled when NETA was associated.

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

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 estrogen-like 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, cell-associated 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 3beta,5alpha- and 3alpha,5alpha-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 5alpha-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.

Effects of estradiol alone and combined with norethisterone acetate on pulse-wave velocity in hypertensive postmenopausal women.

BACKGROUND: Arterial hypertension and postmenopausal reduction of estrogen levels may be involved in modifications of the stiffness of large arteries. OBJECTIVES: To evaluate the pulse-wave velocity (PWV) and indirectly the arterial stiffness in hypertensive postmenopausal women submitted to hormone therapy with estradiol alone or combined with norethisterone acetate. SUBJECTS: Forty-five hypertensive postmenopausal women were double-blindly, randomly assigned to three arms of treatment: placebo (group I); estradiol 2 mg/day (group II); or estradiol 2 mg/day and norethisterone acetate 1 mg/day (group III). METHODS: Arterial stiffness was assessed from PWV measurements of the common carotid and femoral arteries (CF-PWV) and the common carotid and radial arteries (CR-PWV) obtained using the automatic Complior(R) device, taken at baseline and after 12 weeks of treatment. RESULTS: After the 12-week treatment, values of CF-PWV and CR-PWV were not significantly different (p = 0.910 and p = 0.736, respectively) among the groups. Systolic blood pressure showed a positive correlation with CF-PWV in groups II and III (p = 0.02 and p < 0.001, respectively). CONCLUSIONS: PWV and arterial stiffness in postmenopausal hypertensive women did not reduce over a 12-week treatment with estradiol alone compared with the same period of treatment with estradiol combined with norethisterone acetate.

Evaluation of mammographic density and (99m)Tc-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy.

OBJECTIVE: To evaluate changes in mammographic density and (99m)Tc-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy (HRT). METHODS: Seventy-five postmenopausal women were prospectively studied and allocated into three groups: 50 women were randomized to either Group 1 (G1, n=25), which received 2mg of 17beta-oestradiol continuously combined with 1mg of norethisterone acetate (E2/NETA, Kliogest, Medley) or Group 2 (G2), which received 2.5mg/day of tibolone (Livial, Organon). The remaining 25 women, who were asymptomatic and had no desire to undergo HRT, constituted the control group (G3). Each patient was submitted to both mammography and scintimammography at baseline and after six months. Mammographic density was evaluated by using the BI-RADS classification system. The classification system of Barros et al. was used in the interpretation of scintimammography. For statistical analysis, the Chi-square test, ANOVA and Pearson's correlation were used. RESULTS: At six months, increased mammographic density was observed in 48% of G1, 12% of G2 and 16% of G3 patients (p<0.001). The increase in sestamibi uptake was 56% in G1, 28% in G2 and 24% in G3 (p<0.001). Increases in both density and uptake were significantly higher in the group on E2/NETA than among tibolone users and the controls. CONCLUSION: In postmenopausal women, HRT with E2/NETA was associated with increased mammographic density and increased (99m)Tc-sestamibi scintimammographic uptakes, suggesting greater mithochondrial activity in the cells of the mammary duct. This was not observed in users of 2.5 mg of tibolone, demonstrating that the effects on the breast were reduced. The same was observed in the control group.

Inhibition of the acrosome reaction (AR) and fertilization capacity of mouse spermatozoa by norethisterone A-ring reduced metabolite (5alpha-NET).

The contra gestational effects of norethisterone and its main metabolites, 5alpha-NET and 3beta5alpha-NET, has been demonstrated in several species. However, the focus has been mainly on their effects in the uterus. We previously reported that 5alpha-NET inhibits the progesterone-induced AR in pig spermatozoa and induces severe morphological damage to fertilized mouse oocytes. In the present study, we analysed the effects of these compounds on the fertilization process in vitro. Oocytes and spermatozoa were obtained from Balb/c female and C57BL/6J male mice, respectively. Both, the AR assays and the fertilization experiments were performed under different steroid treatment schemes using progesterone as a control. Results showed that norethisterone induced the AR, while 5alpha-NET reduced the percentage of spermatozoa that had undergone progesterone-induced AR. Both 17beta-estradiol and 3beta5alpha-NET induced the AR in a considerably lower percentage of spermatozoa than progesterone. In addition, when 5alpha-NET was added to the medium simultaneously with progesterone at the moment of fertilization, the percentage of fertilized oocytes (two-cell stage) decreased by as much as 77% as compared with the control progesterone-treated group. All results suggest that these compounds can have important effects on the fertilization process.

Hormone replacement therapy does not affect the 24-hour heart rate variability in postmenopausal women: results of a randomized, placebo-controlled trial with two regimens.

Postmenopausal women are at greater risk of coronary heart disease. The results of previous studies of the effects of hormone replacement therapy (HRT) on cardiac autonomic modulation in postmenopausal women have been contradictory. This study examined whether continuous treatment for 3 months with estradiol alone (ERT) or with estradiol plus norethisterone (HRT), increases 24-hour heart rate variability (HRV) in postmenopausal women. In this double-blind, placebo-controlled trial, 40 healthy postmenopausal women, 46-63 years of age, were randomly assigned to (1) continuous 2 mg of estradiol plus 1 mg of norethisterone acetate daily (HRT, n = 13), or (2) 2 mg of estradiol daily (ERT, n = 14), or (3) placebo (n = 13). Before and after 3 months of therapy, blood estradiol concentrations were measured and 24-hour electrocardiograms recorded for evaluation of 24-hour time-domain indices of HRV, and indices derived from the three-dimensional return map. Both hormone replacement regimens significantly increased blood estradiol concentrations, while no change occurred in the placebo group. In the three treatment groups, multiple 24-hour time-domain indices of HRV and indices derived from the three-dimensional return map remained unchanged. In healthy postmenopausal women, HRT with estradiol or estradiol and norethisterone for 3 months did not modify cardiac autonomic activity evaluated by 24-hour indices of HRV. These findings are consistent with a lack of protective cardiovascular effect of HRT described in recent large randomized trials.

Effect of previous hormone replacement therapy on endometrial polyps during menopause.

The aim of this study was to evaluate the effect of hormone replacement therapy (HRT) on the expression of Ki-67, bcl-2 and c-erb.B2 in endometrial polyps during menopause. Sixteen patients using HRT and 24 untreated controls with endometrial polyps were enrolled in this study. Polypectomy was carried out by hysteroscopy. The presence of c-erb.B2, bcl-2 and Ki-67 expression was determined by immunohistochemistry. HRT was found to decrease Ki-67 and bcl-2 expression in endometrial polyps without affecting the c-erb.B2 staining reaction. HRT may cause endometrial polyp involution by decreasing proliferation and stimulating apoptosis.

Progesterone abolishes estrogen and/or atorvastatin endothelium dependent vasodilatory effects.

UNLABELLED: This double blind randomized placebo controlled study assessed the effects of atorvastatin, estradiol and norethisterone, isolated and in combination, on the lipid profile and on vascular reactivity, in post-menopausal women with hypercholesterolemia and arterial hypertension. Ninety-four women aged 50-65 were selected. All have received dietary counseling (4 weeks), placebo (4 weeks), and drug therapy (12 weeks): 17-beta estradiol 2mg/day (E) (n=17); E + norethisterone acetate 1mg/day (P) (n=18); Atorvastatin 10mg/day (A) (n=20); E + A (n=21) and E + P + A (n=18). All treatment modalities have significantly reduced total cholesterol (TC) (E=8.8%, E + P=10.1%, A=27.9%, A + E=29.4% and E + P + A=35.7%) and LDL-cholesterol (LDL-c) levels (E + P + A=46.6%, E + A=45.9%, A=40.2%, E=20.3%, and E + P=12.1%). As concerns HDL-cholesterol (HDL-c), Groups E and E + A had increases of 15.5% and 13.1%, respectively. The addition of a progesterone compound reduced its concentration (Group E + P=-9.1%, and Group E + P + A=-9.5%). By random, approximately half of the patients in each group were designated to the endothelial function evaluation (brachial artery ultrasound). We observed that in Group A (n=10), in Group E (n=10) and with the association (Group E + A) (n=7), there was a significant increase in the flow-mediated vasodilatation as compared to basal measurements. The addition of a progestin has annulled these benefits. CONCLUSIONS: Atorvastatin has promoted more beneficial effects on TC and LDL-c, whereas estradiol was responsible for an increase in HDL-c. The addition of a progesterone derivative abolished these benefits. Atorvastatin, estradiol or both together improved endothelial function, an effect suppressed by the addition of norethisterone.

Comparative evaluation of androgen and progesterone receptor transcription selectivity indices of 19-nortestosterone-derived progestins.

Synthetic 19-nortestosterone-derived progestins show affinity for the androgen receptor (AR) and retain varying degrees of androgenic activity. In this study, AR- and progesterone receptor (PR)-dependent transcriptional activation induced by norethisterone (NET), levonorgestrel (LNG) and gestodene (GSD), and their 5alpha-reduced derivatives, including limited trypsin digestion of AR in the presence of natural and synthetic progestins were investigated. The results confirmed the progestogenic activity of the three 19-nortestosterone derivatives, which decreases after reduction of the 4-ene-double bound. These compounds were able to activate AR-dependent reporter gene expression, LNG and GSD being the stronger activators. 5alpha-Reduction of LNG and GSD did not change their androgenic transcriptional activity; however, the activation of AR by 5alpha-NET was four-fold higher than NET. The highest selectivity transcriptional index, as a measure of progestogenicity versus androgenicity, was obtained for NET. The 5alpha-reduced derivatives had values significantly lower than those of their parent compounds. Non-reduced and 5alpha-reduced 19-nortestosterone progestins induced virtually identical proteolysis fragmentation patterns of the AR to those observed with DHT.

Carotid and uterine vascular resistance in short-term hormone replacement therapy postmenopausal users.

OBJECTIVE: To compare the short-term effects of oral hormone replacement therapy (HRT) and placebo on carotid and uterine vascular impedance. METHODS: 80 postmenopausal women selected from the outpatient clinic of the Hospital Leonor Mendes de Barros in São Paulo, Brazil, were randomized to oral HRT (estradiol 2 mg/norethisterone acetate 1 mg-Kliogest(r)) or placebo. Carotid and uterine arteries pulsatility indices (PIs) were assessed by color Doppler at baseline, after 4 and 12 weeks of treatment. Seventy-six women completed the trial, 38 in each group. RESULTS: The carotid PI did not decrease significantly in either group. In the uterine arteries, the drop in PI was steeper and greater for HRT women. Drops occurred despite the supposed counteracting effect of norethisterone acetate. In placebo group, there was no significant difference between 4 and 12 weeks of treatment compared with the baseline. The results did not change when analyzed in a real treatment approach. CONCLUSION: Oral continuous HRT are effective at 12 weeks in reducing impedance to flow in uterine, but not in carotid circulation. These results suggest that the effects of HRT vary by vascular site, and do not have a detectable short-term vascular effect in the carotid area.

Vasodilating effect of norethisterone and its 5 alpha metabolites: a novel nongenomic action.

Estrogens are generally administered in hormone replacement therapy in combination with synthetic progestins. Studies of cardiovascular risk factors in postmenopausal women have shown a variety of responses according to the molecular structure of the progestin used in hormone replacement therapy schemes. The present study sets out to determine the vasoactive effects of norethisterone and its 5alpha-dihydro (5alpha-norethisterone) and -tetrahydro (3alpha,5alpha-norethisterone and 3beta,5alpha-norethisterone) metabolites in isolated precontracted rat thoracic aorta. The addition of norethisterone and 3alpha,5alpha-norethisterone in rat aorta exhibited a potent, concentration-response inhibition of noradrenaline-induced contraction, while 5alpha- and 3beta,5alpha-norethisterone had very little, if any, vasorelaxing effect. Relaxation to norethisterone and 3alpha,5alpha-norethisterone had very rapid time-courses and it was neither affected by the absence of endothelium nor by the inhibitor of nitric oxide synthase, Nomega-nitro-L-arginine methyl ester (L-NAME). The addition of specific anti-androgen, anti-progestin and anti-estrogen compounds and protein synthesis inhibitors did not preclude the vasorelaxing effect of norethisterone and its 3alpha,5alpha-reduced metabolite. The results strongly suggest that these effects are not mediated by nuclear sex steroid hormone receptors. The overall data document a novel nongenomic endothelium-independent vasorelaxing action of a 19-nor synthetic progestin and one of its A-ring-reduced derivatives.

Norethisterone is bioconverted to oestrogenic compounds that activate both the oestrogen receptor alpha and oestrogen receptor beta in vitro.

In the present study, we used [3H]norethisterone to explore the bioconversion of this compound to A-ring reduced metabolites in African Green Monkey Kidney CV-1 cells and breast cancer T-47D cells. Additionally, we analyzed the capability of each norethisterone tetrahydro-reduced compound to bind the human oestrogen receptors alpha and beta and transactivate an oestrogen-sensitive reporter gene. The results showed that norethisterone is mainly metabolized to 3 alpha,5 alpha-norethisterone (>85% of total [3H]norethisterone added) by CV-1 and T-47D cells, and that both A-ring tetrahydro-reduced metabolites exhibit different capabilities to displace [3H]17beta-oestradiol from the oestrogen receptor alpha and beta, being 3 alpha,5 alpha-norethisterone the weakest competitor. We also found that 3 alpha,5 alpha-norethisterone and 3beta,5 alpha-norethisterone activate both oestrogen receptors at nanomolar concentrations and that the transactivation induced by the oestrogen receptor alpha was generally higher (1.7- to 4.0-fold) than that provoked by the beta receptor isoform. In oestrogen receptor alpha-transfected CV-1 and T-47 D cells, the oestrogenic-like potency of the 3beta,5 alpha-tetrahydro-reduced form was similar to that exhibited by 17beta-oestradiol and 2.5- to 4.0-fold higher than that shown by the 3 alpha,5 alpha-reduced compound; conversely, in the oestrogen receptor beta system the potency of the natural ligand was higher than that presented by the 3beta,5 alpha-tetrahydro-reduced metabolite. In CV-1 cells expressing the oestrogen receptor beta, the transactivation potency of 3beta,5 alpha-norethisterone was approximately 2-fold higher than that exhibited by its 3 alpha,5 alpha-tetrahydro-reduced isomer, whereas in T-47D cells the potency of the 3 alpha,5 alpha-tetrahydro-reduced compound was slightly higher than that shown by the 3beta,5 alpha A-ring reduced norethisterone metabolite. These results demonstrate that CV-1 and T-47D cells possess the enzymatic machinery to bioconvert norethisterone into the 5 alpha-reduced, 3 alpha-hydroxylated form and that neither 3 alpha,5 alpha- or 3beta,5 alpha-norethisterone exhibit preference or selectivity towards a particular oestrogen receptor isoform to induce a particular oestrogenic effect in these cell lines.

Acceptability and patterns of endometrial bleeding in estradiol-based HRT regimens: a comparative study of cyclical sequential combinations of trimegestone or norethisterone acetate.

OBJECTIVE: This randomized, double-blind, multicenter study was planned to compare the efficacy and tolerance of a novel oral regimen containing estradiol (2.0 mg) sequentially combined with trimegestone, at a daily dose of either 0.25 mg or 0.5 mg, with a standard hormone replacement therapy containing estradiol and norethisterone acetate (E2 + NETA) in the treatment of climacteric symptoms. METHODS: The study was conducted over 13 cycles, each of 28 days, and involved 487 subjects, of whom 349 completed the study. RESULTS: All three treatments were equally effective in alleviating hot flushes and showed a progressive and significant reduction in the value of the Kupperman index. The treatments diminished equally effectively urogenital signs and symptoms. All treatments were well tolerated and the incidences of adverse events associated with each treatment were similar across the treatment groups. The duration of expected withdrawal bleeding was shorter in the estradiol + trimegestone 0.5 mg group than in the estradiol + trimegestone 0.25 mg or E2 + NETA group. CONCLUSION: All treatments were effective and well tolerated, providing significant relief from climacteric symptoms. Treatment with estradiol + trimegestone 0.5 mg provided the most favorable bleeding pattern.

Variations of progesterone receptor and c-fos gene expression in the rat uterus after treatment with norethisterone and its A-ring reduced metabolites.

It has been suggested that some contraceptive derivatives of 19-nor-testosterone possess estrogenic activity that may facilitate the development of breast cancer. The aim of this work was to investigate the estrogenic properties of norethisterone (NET) and its A-ring-reduced derivatives by determining progesterone receptor (PR) and c-fos mRNA content of two estrogen-regulated genes in the uterus of ovariectomized rats. mRNA content was evaluated by Northern blot 1-6 h after 17 beta-estradiol administration. The highest PR and c-fos mRNA content was observed 3 h and 2 h after 17 beta-estradiol administration, respectively. NET did not modify either PR or c-fos mRNA content. In contrast, 5 alpha- and 3 beta, 5 alpha-NET significantly increased mRNA content of both genes. The increase in c-fos mRNA content induced by these reduced compounds was lower than that found with estradiol treatment. The overall results indicate that NET administration can indirectly induce estrogenic effects through the action of its 5 alpha-dihydro and 3 beta, 5 alpha-tetrahydro derivatives.

The androgenic effect of norethisterone and 5alpha-norethisterone on the contractile response of the rat vas deferens to methoxamine and serotonin.

Norethisterone (NET) and its metabolite 5alpha-norethisterone (5alpha-NET) are competitors for the androgen receptor. The sensitivity of the rat vas deferens to the contractile action of methoxamine and serotonin is regulated by hormonal and anatomical factors. The aim of this study was to evaluate the ability of NET and 5alpha-NET to induce the androgen-regulated contractile response to methoxamine and serotonin in the epididymal and prostatic portions of rat vas deferens. Adult male rats either intact, castrated or steroid-treated castrated were used. The contractility was recorded isometrically, and non-cumulative concentration-response curves to either methoxamine or serotonin were obtained. NET and 5alpha-NET partially restored the sensitivity to methoxamine and serotonin in the epididymal portion of castrated rats. The maximal responses to both agonists were significantly higher than those observed in castrated rats, and significantly lower than the responses observed in either intact or androgen-treated castrated rats. The prostatic portion was less responsive to both agonists than the epididymal portion, in all groups but castrated rats, as castration induced sensitivity to both agonists. NET and 5alpha-NET displayed a partial though similar androgenic activity in the rat vas deferens. These results contrast with previous reports where a decrease of androgenic effect due to the 5alpha-reduction of NET has been found.