Preclinical and clinical properties of trimegestone: a potent and selective progestin.

Trimegestone (TMG) is a novel, 19-norpregnane progestin with potent and selective properties. In preclinical studies, TMG has been shown to provide high endometrial selectivity. Further, TMG has high affinity and selectivity for the progesterone receptor and lacks the agonist effects of other steroid hormones. In clinical studies, TMG has been shown to have high endometrial safety and an improved bleeding profile along with improved tolerability compared with other progestins. In addition, TMG also does not impede the beneficial effects of estrogen, especially on bone, and does not compromise quality of life. The preclinical findings of lack of mineralocorticoid activity of TMG were supported in clinical findings, with neutral effect on body weight. Similarly, the smaller effect of TMG on the GABA-ergic (gamma-aminobutyric acid) system in preclinical studies is consistent with the improvement of central nervous system-related effects on depressed mood and sleep quality in clinical studies. Low-dose estradiol/TMG regimens provide rapid relief from menopausal symptoms, reducing the number and severity of hot flushes as effectively as 2 mg 17beta-estradiol/1 mg norethisterone acetate. Therefore, it may be concluded that TMG provides a clinically proven option in hormone therapy for both clinicians and patients.

Bleeding profile and endometrial safety of continuous combined regimens 1 mg 17beta-estradiol/trimegestone versus 1 or 2 mg 17beta-estradiol/norethisterone acetate in postmenopausal women.

OBJECTIVE: To compare the bleeding profile and endometrial safety of continuous combined 1 mg 17beta-estradiol (17beta-E2) and 0.125 mg trimegestone (TMG) with those of two continuous combined 17beta-E2 and norethisterone acetate (NETA) regimens. STUDY DESIGN: This was a double-blind, randomized, multicenter study conducted in 12 European countries and Israel over a 2-year period. Healthy postmenopausal women with an intact uterus were given either 1 mg 17beta-E2/0.125 mg TMG, 2 mg 17beta-E2/1 mg NETA or 1 mg 17beta-E2/0.5 mg NETA for up to 26 cycles, each of 28 days. RESULTS: The percentage of amenorrheic women was greater in most cycles up to cycle 13 in the 1 mg 17beta-E2/0.125 mg TMG group than in the comparator groups. The mean number of bleeding days was similar in the 1 mg 17beta-E2/0.125 mg TMG and the 1 mg 17beta-E2/0.5 mg NETA groups, but greater in the 2 mg 17beta-E2/1 mg NETA group. No endometrial hyperplasia was observed for any group. CONCLUSION: Continuous combined 1 mg 17beta-E2/0.125 mg TMG exhibits a more favorable bleeding profile than 1 mg 17beta-E2/0.5 mg NETA up to 1 year, while providing an adequate protective effect on the endometrium.

A comparative 2-year study of the effects of sequential regimens of 1 mg 17beta-estradiol and trimegestone with a regimen containing estradiol valerate and norethisterone on the bleeding profile and endometrial safety in postmenopausal women.

OBJECTIVE: To compare the bleeding profiles and endometrial protection of two sequential regimens of 17beta-estradiol (17beta-E2) and trimegestone (TMG) with a sequential estradiol valerate (E2V)/norethisterone (NET) regimen. STUDY DESIGN: This was a randomized, double-blind, multicenter study conducted in eight countries in healthy, postmenopausal women with an intact uterus. A total of 1218 women were enrolled into the initial 1-year study (13 cycles), and subsequently 531 of these received treatment for a further year (26 cycles). Treatment regimens were 1 mg 17beta-E2 on days 1-14 and 1 mg 17beta-E2/0.125 mg TMG or 1 mg 17beta-E2/0.25 mg TMG on days 15-28, and 1 mg E2V on days 1-16 and 1 mg E2V/1 mg NET on days 17-28. RESULTS: Mean percentage of women reporting onset of withdrawal bleeding episodes during the week following discontinuation of progestogen was higher in the 1 mg 17beta-E2/0.25 mg TMG group than in the other two treatments, showing a more efficient progestogen effect on the endometrium and good predictability of bleeding onset with this treatment. The mean numbers and average lengths of bleeding episodes were similar in the three treatment groups. Overall, the bleeding profile was more favorable with 1 mg 17beta-E2/0.25 mg TMG than with the lower-dose TMG preparation. Both of the TMG regimens demonstrated a good protective effect on endometrial proliferation, with the 0.25 mg TMG dose showing a lower incidence of proliferative endometrium. CONCLUSION: The 1 mg 17beta-E2/0.25 mg TMG regimen showed an adequate protection of the endometrium, with an overall favorable bleeding profile.

One year comparison between two add-back therapies in patients treated with a GnRH agonist for symptomatic endometriosis: a randomized double-blind trial.

BACKGROUND: It has been proposed that hormonal supplementation during prolonged GnRH agonist therapy prevents hypoestrogenic side effects, including bone loss. The optimal combination for long-term treatments with safe metabolic profile remains questionable. A norprogesterone derivative, promegestone, was assessed for the first time in a double-blind trial. METHODS: Seventy-eight patients with endometriosis with rAFS (Revised American Society for Reproductive Medicine) scores of III-IV were randomly assigned to monthly leuprorelin 3.75 mg (1 year) which, after the third injection was used in combination with promegestone 0.5 mg (P) plus either estradiol placebo (PL) or estradiol 2 mg (E) per day. Bone mineral density (BMD) was determined at baseline, 6 and 12 months, and biological and clinical quarterly assessments were performed. Analysis was by the intention to treat method. RESULTS: At month 12, BMD changes from baseline were -6.1 +/- 3.7 and -4.9 +/- 4.0% in the PL-P group, at the spine and hip, respectively. This bone loss was prevented in the E-P group: -1.9 +/- 3.1 and -1.4 +/- 2.3%, respectively (P < 0.0001 inter-group comparisons). The BMD decrease in the E-P group was explained by the changes occurring during the first 6 months of treatment. There was no deleterious change in lipid parameters. Clinical improvement was observed without an inter-group difference. CONCLUSIONS: Estradiol 2 mg and promegestone 0.5 mg per day is an effective and safe add-back therapy, which can be proposed for prolonged leuprorelin treatment over 6 months in severe endometriosis.

Increased resistance to activated protein C after short-term oral hormone replacement therapy in healthy post-menopausal women.

As hormone replacement therapy is associated with an early excess risk of venous thrombosis, we investigated the effect of different oral hormone replacement therapies on resistance to activated protein C, and on levels of factor VIII antigen (FVIII:Ag) and factor XI antigen (FXI:Ag). In a prospective, randomized, placebo-controlled 12-week study, 60 healthy post-menopausal women daily received either placebo (n = 16) or 2 mg of micronized 17beta-oestradiol, either alone (E2, n = 16) or sequentially combined with dydrogesterone 10 mg (E2 + D, n = 14) or trimegestone 0.5 mg (E2 + T, n = 14). Medication was given orally. Normalized activated protein C sensitivity ratios (nAPCsr) were determined by quantifying the effect of activated protein C on the endogenous thrombin potential. FVIII:Ag and FXI:Ag were determined by enzyme-linked immunosorbent assay. Compared with baseline and placebo, the nAPCsr increased (92% to 142%; all P < 0.001) in all active treatment groups after both 4 and 12 weeks. Compared with placebo, hormone replacement therapy was not associated with significant changes in FVIII:Ag. After 4 and 12 weeks, FXI:Ag levels were significantly decreased in the E2 group (mean percentage changes from baseline versus placebo: -15.0%, P = 0.001 at 4 weeks and -16.6%, P = 0.003 at 12 weeks) and in the E2 + D group (-10.4%, P = 0.02 and -10.4%, P = 0.02). In conclusion, all hormone replacement regimens were associated with a large increase in resistance to activated protein C. In contrast, hormone replacement therapy had no effect on FVIII:Ag. Oral E2 and E2 + D had a small, favourable effect on FXI:Ag.

A 1-year comparison of the efficacy and clinical tolerance in postmenopausal women of two hormone replacement therapies containing estradiol in combination with either norgestrel or trimegestone.

This double-blind, randomized, multi-center study compared the efficacy and clinical tolerance of a combined formulation containing 2 mg estradiol (E2) and 0.5 mg trimegestone (TMG) with a standard hormone replacement therapy containing estradiol valerate (E2V) and norgestrel (NG) in the treatment of climacteric symptoms. The study was conducted over 13 cycles, each of 28 days, and involved 634 subjects, of whom 481 completed the study. The primary efficacy variable was the percentage of subjects who showed at least a 50% reduction from baseline in the mean daily number of hot flushes in cycle 3. This was observed in 98.5% of the subjects in the E2 + TMG group and 93.3% of the subjects in the E2V + NG group (95% confidence interval of the difference, -8.6, -1.9). Significant differences in favor of the E2 + TMG combination were observed in the reduction in the mean daily number and severity of hot flushes, and in the percentage of subjects who had hot flushes at baseline but no hot flushes during treatment. There were no significant differences between the treatments in the Kupperman index and in urogenital signs or symptoms. Treatment with the E2 + TMG combination was well tolerated and the incidences of adverse events were similar in the two treatment groups. Breast pain was the main adverse event, possibly related to treatment that resulted in discontinuation. The mean number of bleeding days per cycle was significantly lower with the E2 + TMG combination than with the E2V + NG combination. The incidences of endometrial hyperplasia were low and comparable in both treatment groups. It was concluded that the E2 + TMG combination was either equivalent or superior to the E2V + NG combination in the treatment of hot flushes and other climacteric symptoms, and that its bleeding profile was favorable.

Trimegestone: expanding therapeutic choices for the treatment of the menopause.

UNLABELLED: Trimegestone is a novel norpregnane progestin, which has a potent progesterone receptor and very low androgen receptor affinities but no detectable affinity to oestrogen receptor. Trimegestone has been developed for use in conjunction with oestrogen for postmenopausal hormone replacement therapy (HRT). The dose of trimegestone required for endometrial safety was optimised in a dose ranging study. Oral trimegestone was administered at 0.05, 0.1, 0.25 and 0.5 mg/day, days 15 - 28 along with continuous oral micronised oestradiol at 2 mg daily. The majority of women in the four dose groups experienced relief of climacteric symptoms by the end of the third treatment cycle. The incidence of pre-menstrual tension-like symptoms was low and did not differ between the four dose groups. After 6 months of treatment, the bleeding pattern showed a clear dose-dependent modulation such that the higher the dose of trimegestone administered the more predictable was the day of onset of bleeding and the shorter and lighter the bleeding episodes became. This was further confirmed in another study comparing trimegestone in 0.5 and 0.25 mg doses to norethisterone acetate, where women on the 0.5 mg dose experienced more favourable bleeding pattern compared with the lower dose of 0.25 mg or to norethisterone acetate. In the dose ranging study, 96% of endometrial specimens obtained at the end of the study had secretory changes. The lipoprotein profile measured at baseline, 3 and 6 months during the dose ranging study confirmed the fact that trimegestone, irrespective of the dose, did not negate the beneficial effects of oestrogen on lipids. CONCLUSION: trimegestone is an effective and well-tolerated new progestin, which does not negate the beneficial effects of oestrogen on lipids.

Acceptability and patterns of uterine bleeding in sequential trimegestone-based hormone replacement therapy: a dose-ranging study.

Trimegestone is a norpregnane progestogen which is being developed in combination with oral oestradiol as postmenopausal hormone replacement therapy (HRT). In this multicentre dose-ranging study using randomized parallel groups, four doses of trimegestone were used to compare data on the patterns of uterine bleeding, the endometrial histology, and the control of menopausal symptoms in 203 women who completed treatment for 6 months. The treatment consisted of micronized oestradiol (2 mg/day) and one of four doses of trimegestone, which was administered sequentially for days 15-28 of the treatment cycle. Higher doses of trimegestone were associated with later onset of bleeding, which was lighter and of shorter duration than that observed with lower doses. The variability of the day of onset of bleeding in individual women was greater when bleeding occurred before the end of the progestogen phase (early bleeders) than when it occurred afterwards (late bleeders). All women enrolled in the study experienced good control of menopausal symptoms, with minimal progestogenic adverse effects, there being no statistically significant difference between the four dose groups.

Endometrial effects of three doses of trimegestone, a new orally active progestogen, on the postmenopausal endometrium.

OBJECTIVE: To study the effects of oral trimegestone on endometrial histology and vaginal bleeding when given in combination with oral 17-beta-oestradiol. METHODS: This was a prospective, randomised, double-blind, parallel groups, pilot comparative study. Thirty-eight healthy postmenopausal women with normal endometrial histology were given oral 17-beta-oestradiol, 2 mg/day for three continuous cycles of 28 days, plus oral trimegestone, 0.10, 0.25 or 0.50 mg/day from day 15 to day 28 of each cycle. A Vabra biopsy was performed late in the oestradiol/trimegestone phase of cycle 3 and examined for histological evidence of secretory transformation of the endometrium. Characteristics of vaginal bleeding were recorded on a daily basis. RESULTS: Thirty-seven women completed the study, of whom 31 yielded adequate tissue for histological assessment. All showed secretory transformation of the endometrium. Bleeding was of earlier onset and longer duration with the lowest dose of trimegestone. CONCLUSIONS: Trimegestone is a highly effective oral progestogen for endometrial protection, all doses inducing secretory endometrial transformation. Although bleeding patterns suggest a weaker effect of the lowest dose used, the minimum effective dose for endometrial protection has still to be determined and may be lower than those used in this study.

[Female contraception by a normal dose progestogen after 40 years of age. Possible association of nomegestrol--17-beta-estradiol acetate by percutaneous route]. / La contraception féminine par progestatif normodosé après 40 ans. Possibilité d'association acétate de nomégestrol--17-bêta-estradiol par voie cutanée.

Although fertility declines with age, the use of an effective contraceptive remains necessary in women over 40. Endocrine disorders, which are common in this age group, may also often require control. Conventional estroprogestogens, even those of the latest generation, cannot be used in women with a high cardiovascular risk, since age cannot be totally excluded as a possible risk factor. The contraceptive use of derivatives of 17-hydroxyprogesterone and 19-norprogesterone offer a promising alternative, despite the absence of any exhaustive investigation particularly in situations in which the blood level of estradiol has to be reduced. There are, however, some women who respond to this type of contraception by menstrual cycle irregularities, and sometimes by low blood levels of estradiol, regardless of the drug used. A preliminary study is described in which 5 mg of nomegestrol acetate was combined with 17-beta-estradiol by transcutaneous route and which has so-far demonstrated sustained contraceptive efficacy as well as excellent clinical and metabolic safety.

Double-blind trial of promegestone (R 5020) and lynestrenol in the treatment of benign breast disease.

One hundred thirty-two women between the ages of 19 and 50, with various forms of benign breast diseases received 1 mg promegestone, or 0.5 mg promegestone, or 10 mg lynestrenol daily (double-blind), for 15 days per cycle, during three cycles. The groups were identical before treatment, with the exception of a longer history of mastodynia and mastopathies in the 1 mg promegestone group than in the lynestrenol group (P = 0.04) and a greater proportion of mastosis zones in the lynestrenol group as compared to the 0.500 mg promegestone group (P = 0.05). The effectiveness of lynestrenol both in terms of symptomatology (evaluated as good or excellent in 66.6% of the cases) and of clinical observations (evaluated as good or excellent in 59% of the cases) is not significantly different statistically from that of promegestone at 1 mg, whose effectiveness on symptomatology was good or excellent in 65.9% and 57.1% of the cases, respectively, or from that of promegestone at 0.5 mg/day (with 65% and 51.3% effectiveness, respectively). Clinical tolerance was rated good or excellent for 73.9% of the women on 1 mg promegestone and for 59.5% of the women on 0.500 mg promegestone, compared to 66.7% of the women on lynestrenol. No statistically significant difference was observed, neither between lynestrenol and promegestone 1 mg nor between lynestrenol and promegestone 0.5 mg. This study shows a clear improvement in functional and physical signs in patients treated with promegestone. Promegestone's efficacy is close to that of lynestrenol, a nonsteroidal progestin.2+ off