Single-dose pharmacokinetics and pharmacodynamics assessment of oestriol and trimegestone containing vaginal rings in healthy women with childbearing potential.

PURPOSE: To evaluate the pharmacokinetics and pharmacodynamics of oestriol (E3) and trimegestone (TMG) in healthy women after application of three different vaginal rings over 21 days. The vaginal rings had a nominal delivery rate of 0.413/0.050 mg/day (Test 1), 0.311/0.090 mg/day (Test 2) and 0.209/0.137 mg/day (Test 3) E3/TMG. METHODS: Thirty-five healthy women were randomised to receive a single application of Test 1, 2 or 3 (Clinical Trial NCT03343912). The E3 and TMG plasma concentration was determined by LC-MS/MS. Oestradiol (E2) and progesterone (PG) serum concentrations, and bleeding patern were determined as pharmacodynamic parameters. Safety was assessed by evaluation of adverse events and local tolerability. RESULTS: The total and maximum exposure of E3 and TMG increased in a proportional ratio to dose. However, not in a magnitude which was expected from the dose differences for E3. During Test 2 and 3 treatment all E2 and PG values remained on a well suppressed level until end of treatment. E2 and PG serum levels increased distinctly earlier after ring removal with Test 1 compared to Test 2 and 3. Test 3 achieved 95.24% of "no bleeding" days under treatment followed by Test 1 (91.67%), and Test 2 (86.15%). CONCLUSIONS: The Test 3 formulation presented the best dose combination of E3/TMG for contraception. Moreover, all vaginal rings were well tolerated.

A randomized, controlled pilot trial of hormone therapy for menopausal insomnia.

Insomnia is a frequent climacteric symptom. This pilot, double-blind, randomized placebo-controlled trial compared estradiol associated with trimegestone or placebo in 12 women with perimenopausal insomnia. The Pittsburgh Sleep Quality Index (PSQI) was administered, and polysomnography was performed at baseline and after 28 days. Sleep efficiency and median score of the PSQI improved significantly in the hormone therapy group (HT) (p=0.041 and p=0.027, respectively) and not in placebo group. Perimenopausal insomnia improved after short-term HT.

Ovulation inhibition with a new vaginal ring containing trimegestone.

OBJECTIVES: The primary objective was to determine the lowest trimegestone (TMG) dose, administered via a vaginal ring, that effectively inhibited ovulation. STUDY DESIGN: Single-centre, open-label, single-dose, parallel-group clinical trial with adaptive design. Eighty healthy female volunteers with proven ovulatory cycles were allocated to treatment with a vaginal ring during 28 days, with an average daily release rate of either 46 µg, 94 µg, 147 µg, or 184 µg TMG (20 women/group). Ultrasound measurements of follicular growth and endometrial thickness, and blood sampling for follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone determinations were performed every 3rd (±1) day from treatment day 4 (±1) until day 28 (±1), and in a follow-up phase after ring removal, until study day 39 (±1). Trimegestone concentrations were measured at each visit in the treatment phase. RESULTS: Mean age and body mass index were 28.8 years and 23.15 kg/m2. One subject in the lowest dose group (46 µg/day) ovulated, no ovulations were seen in the higher dose groups. The degree of ovarian suppression increased with the dose. Median estradiol levels were 119, 36.5, 33.2 and 27.2 pg/mL in the 46, 94, 147 and 184 µg/day groups, respectively. Ovarian activity was resumed in the follow-up phase. Plasma TMG levels gradually declined over the treatment period and showed dose proportionality. The study treatment was safe and well tolerated. CONCLUSION: The release rate of 94 µg TMG per day was the lowest effective dose for ovulation inhibition. The study results justify further development of the TMG-ring as progestogen-only contraceptive. IMPLICATIONS: The vaginal ring releasing TMG seems to be an effective new progestogen-only contraceptive preparation, having the advantage of once-a-month vaginal insertion.

Inhibitors and activation markers of the haemostatic system during hormone therapy: a comparative study of oral estradiol (2 mg)/ dydrogesterone and estradiol (2 mg)/ trimegestone.

Epidemiological studies have shown that hormone therapy (HT) increases the risk of venous thromboembolism in post menopausal women. The mechanism of this increased risk is unknown; however, activation of the haemostatic system is known to contribute to the pathogenesis of venous thromboembolism. In post-menopausal women the estrogen/progestogen composition of the HT can influence the level of haemostatic activation. It was the objective of this study to compare changes in inhibitors and activation markers of the haemostatic system in healthy post-menopausal women taking estradiol (2 mg) combined with dydrogesterone or a new progestin, trimegestone. A multicentre study of 186 women randomised to six months therapy with either estradiol (2 mg) +trimegestone (0.5 mg) or estradiol (2 mg) +dydrogesterone (10 mg) was performed. Antithrombin and protein S activity was decreased and activated protein C (APC) resistance, D-dimer and prothrombin fragment 1.2, were increased in both groups on treatment. Protein C activity was decreased and plasmin-antiplasmin complex was increased in the trimegestone group only. The increase in plasmin-antiplasmin complex and D-dimer was greater after six cycles of treatment in the trimegestone group compared with the dydrogesterone group. In conclusion, decreased levels of inhibitors of blood coagulation and increased thrombin production were found in both groups however a greater increase in the levels of plasmin-antiplasmin complex and D-dimer was found in the trimegestone group. This suggests an enhanced fibrinolytic response in this group. Further studies are required to determine the significance of this finding with respect to venous thrombosis risk.

Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat.

Oral contraceptives (OC) and postmenopausal hormone therapy (HT) modulate plasma levels of proteins that regulate blood coagulation. It remains unclear whether the progestin component contributes to these changes. The present study was designed to determine whether progestins modulate two essential plasma anticoagulants, antithrombin (AT) and tissue factor pathway inhibitor (TFPI), in an animal model. Ovariectomized rats were treated orally with three progestins, norethindrone acetate (NETA), trimegestone (TMG), or drospirenone (DSP), either alone or combined with 17alpha-ethyinylestradiol (EE). Plasma AT levels were unchanged. However, TFPI activity was reduced by EE alone (10-100 microg/kg/day) in a dose-dependent manner; NETA (3 or 10 mg/kg/day) reduced TFPI by approximately 40 or approximately 80%, respectively, while TMG and DSP had no effect. NETA and EE effects were blocked by co-administration of ICI-182,780, an estrogen receptor antagonist, suggesting that both responses were likely estrogen receptor-mediated. Reduced TFPI after NETA or EE treatment was not accompanied by changes in TFPI mRNA levels in tissues that express TFPI, but there was a positive correlation between plasma TFPI and total cholesterol. Sex hormone effects on TFPI in this model and as reported in women may help to shift the coagulation balance to a more prothrombotic state. Progestins such as TMG and DSP that lack estrogenic activity could potentially have an improved clinical profile.

Quantitative analysis of gene regulation by seven clinically relevant progestins suggests a highly similar mechanism of action through progesterone receptors in T47D breast cancer cells.

Progesterone (P4) is an essential reproductive steroid hormone required for many aspects of female reproductive physiology. Progestins are compounds that demonstrate progesterone-like activity and are used in oral contraception, hormone therapy, and treatment of some reproductive disorders, but differ widely in their chemical structures, potency, and pharmacokinetics. While numerous studies have assessed progestins on specific endpoints, little is known about the activation of global gene expression by progestins. We used Affymetrix GeneChip U133A expression arrays to examine the action of P4 and six clinically relevant synthetic progestins (3-ketodesogestrel, drospirenone, levonorgestrel, medroxyprogesterone acetate, norethindrone acetate, and trimegestone) on the progesterone receptor (PR)-positive T47Dco and the PR-negative T47D-Y breast cancer cell lines. Excluding drospirenone, one or more of the progestins-regulated 329 genes, with 30 genes regulated by at least 2.0-fold by all progestins in the T47Dco cells. The synthetic progestins show a high degree of similarity in their transcriptional responses, and each progestin regulates between 77 and 91% of the genes regulated by P4. Independent quantitative RT-PCR analysis confirmed a similar regulation for S100P, PPL, IL20RA, NET1, ATP1A1, HIG2, and CXCL12 (SDF-1) by all seven progestins. Attempts to find differentially regulated genes by any progestin compared to all other treatments failed, suggesting any differences are quantitative, not qualitative. This analysis demonstrates a high degree of similarity among these progestins on PR-regulated gene expression in T47D cells, suggesting a similar and fairly specific mode of action.

Residues in the ligand binding domain that confer progestin or glucocorticoid specificity and modulate the receptor transactivation capacity.

To localize regions conferring ligand binding specificity of the human glucocorticoid (hGR) and progesterone (hPR) receptors, we constructed chimeras comprising the DNA-binding domain of the yeast transcription factor GAL4, linked to the ligand binding domain of hGR or hPR. Replacement of a sequence of hGR encompassing helices H6 and H7 with the homologous sequence from hPR creates a chimeric protein GP3, which binds the progestin RU 27987 with high affinity, and results in a concomitant loss of glucocorticoid binding [dexamethasone (DEX), RU 43044]. Moreover, GP3 is not able to mediate RU 27987-induced transactivation. A detailed mutational analysis of this sequence and the study of the recently solved hPR crystal structure revealed five residues that confer progestin responsiveness to GR or modulate ligand binding and transcriptional activation. Notably, the simultaneous presence of residues Ser637 and Phe639 on GP3, lining the ligand binding pocket, is specifically involved in RU 27987 binding. The absence of residues Asp641, Gln642, and Leu647 on GP3 is accountable for the lack of glucocorticoids binding on GP3. Unlike residue 642, residues 641 and 647 are not in direct contact with the ligand and most likely act through steric-mediated interactions. The presence of Gln642 and Leu647 are determinant for transcriptional activation in response to DEX and RU 27987, respectively. DEX-dependent transactivation is further enhanced by the presence of Leu647.

Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized, placebo-controlled 12-week study in healthy early postmenopausal women.

In a prospective, randomized, placebo-controlled 12-wk study, we investigated the effect of oral hormone replacement therapy on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), and an independent risk factor for coronary heart disease. The effects on arginine and symmetric dimethylarginine were also investigated. Sixty healthy early postmenopausal women received daily placebo (n = 16) or oral 17beta-estradiol 2 mg, either unopposed (E(2); n = 16) or sequentially combined with dydrogesterone 10 mg (E(2)+D; n = 14) or trimegestone 0.5 mg (E(2)+T; n = 14). ADMA levels reduced in all active treatment groups. Compared with baseline and placebo, the largest reduction in ADMA levels was observed in the E(2)+T group [-18.7% (95% confidence interval [CI], -25.4 to -11.9%) and -21.1% (95% CI, -26.2 to -16.1%), at 4 and 12 wk, respectively]. At 4 and 12 wk in the E(2)+T group, arginine levels were significantly reduced as well [-30.9% (95% CI, -41.1 to -20.7%) and -36.3% (95% CI, -43.1 to -29.5%), respectively], whereas symmetric dimethylarginine levels were significantly lower in the E(2)+D group after 12 wk [-11.6% (95% CI, -19.9 to -3.3%)]. In conclusion, unopposed oral estradiol and estradiol combined with dydrogesterone or trimegestone reduced plasma levels of the NOS inhibitor ADMA. Whether the reduction of the NOS substrate arginine in the E(2)+T group counteracts the potentially beneficial effect of ADMA reduction or reflects increased NO production remains to be investigated.

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.

Trimegestone in a low-dose, continuous-combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women.

OBJECTIVE: To determine the efficacy of estrogen + progestogen therapy with 1 mg 17beta-estradiol and 0.125 mg trimegestone in the prevention of postmenopausal osteoporosis. DESIGN: For this study, 360 healthy, postmenopausal women with osteopenia [lumbar spine bone mineral density (BMD) between -1.0 and -2.5 SD of the premenopausal mean value] were enrolled in a 2-year prospective, randomized study, and 70% completed. Treatments were 1 mg 17beta-estradiol + 0.125 mg trimegestone (n = 179) or placebo (n = 181), given as daily oral therapy. All received a daily supplement of 500 mg calcium and 400 IU vitamin D. BMD measurements at the lumbar spine, total hip, and femoral neck as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin), serum bone-specific alkaline phosphatase, serum CrossLaps, and urinary CrossLaps took place regularly. RESULTS: BMD increases relative to placebo were 6.3%, 3.9%, and 3.8% at the lumbar spine, total hip, and femoral neck, respectively (all P < 0.001). The biochemical markers of bone turnover were suppressed accordingly. Serum CrossLaps and urinary CrossLaps decreased rapidly, by 52% and 54%, respectively, whereas serum osteocalcin and serum bone-specific alkaline phosphatase revealed a more retarded decrease of 40% and 33%, respectively. Of the women receiving hormone therapy, 75% had amenorrhea from the first cycle, and 5% withdrew prematurely due to metrorrhagia or mastalgia. CONCLUSION: This new estrogen + progestogen therapy is efficient in increasing BMD in an osteopenic postmenopausal population. Furthermore, it is well tolerated, with few adverse events and an early bleeding control, which is likely to improve compliance to the treatment over the long term.

Rat uterine complement C3 expression as a model for progesterone receptor modulators: characterization of the new progestin trimegestone.

Progestins have a wide variety of activities in female reproduction. There are also pharmacological applications for progestins, including hormone replacement therapy and contraception. Here we report the development and characterization of the rat uterine complement component C3 mRNA as a molecular target for the evaluation of the antiestrogenic activity of progestins in the uterus. In this assay, ethinyl estradiol (EE) is used to stimulate C3 expression and progestins are then evaluated for their ability to inhibit this expression. The three reference progestins, progesterone (P4), levonorgestrel (LNG), and medroxyprogesterone acetate (MPA) blocked the increase in C3 mRNA levels induced by EE. Dexamethasone (DEX) and 17alpha-methyl testosterone did not inhibit the estrogen induced C3 mRNA levels; in fact, DEX caused a further increase in C3 mRNA levels. Finally, the antiprogestin RU486 was able to block the MPA inhibition of C3 message. RU486, like DEX, caused an increase in C3 mRNA levels above that of estrogen treatment alone. The model was also used to evaluate trimegestone (TMG), a new steroidal progestin, that has been shown to be a potent and selective progesterone receptor agonist. The activity of TMG in the rat uterine decidualization and ovulation inhibition assays was similar to MPA. However, in the C3 model, TMG caused a dose-dependent inhibition of the EE induced C3 message and was approximately five-fold more potent in this model than MPA (EC(50) of 4.7 microg/kg and 26.5 microg/kg, respectively). Therefore, TMG was a more potent antagonist of estrogenic activity in the uterine endometrium than any of the reference progestins tested and therefore may be more effective in protecting the endometrium in hormone replacement therapy.

Hormone replacement therapy and plasma homocysteine levels.

OBJECTIVE: To compare the effects of 4 and 12 weeks of combined estradiol-progestogen replacement with unopposed estradiol therapy on fasting plasma total homocysteine concentrations in healthy postmenopausal women. METHODS: In this prospective, 12-week study in healthy postmenopausal women, we randomly assigned 59 women to sequentially combined daily 2 mg estradiol (E2) plus either trimegestone 0.5 mg daily or dydrogesterone 10 mg daily (n = 28), or to unopposed daily 2 mg estradiol (n = 16), or to placebo (n = 15). RESULTS: Fasting plasma total homocysteine concentrations decreased by 9.4% in the combined estradiol-progestogen group and by 5.1% in the estradiol-only group, and they increased by 2.4% in the placebo group (analysis of covariance: combined hormone replacement therapy compared with placebo (P = .02); combined therapy compared with estradiol (P = .23); and estradiol compared with placebo (P = .26). Reductions were detectable after 4 weeks of combined estradiol-progestogen treatment. The data suggest an additional progestogen-related reduction in homocysteine levels of 0.7 micromol/L and 0.4 micromol/L after 4 and 12 weeks, respectively. Women with a baseline homocysteine concentration in the highest quartile had significantly greater reductions in homocysteine compared with women with an initial homocysteine value in the lowest quartile. CONCLUSION: Fasting total homocysteine concentrations were significantly reduced by combined estradiol-progestogen replacement. Women with high homocysteine levels at baseline benefit the most. The progestogens used in this study did not have an unfavorable effect on homocysteine metabolism.

Evaluation of RU-27987 as a ligand to determine the progesterone receptor.

RU-27987, a synthetic progestin, which was recently developed by Roussel Uclaf, Paris, was tested for its validity as a ligand to determine the progesterone receptor in breast cancer. The results were compared to those obtained with R-5020 and ORG-2058, two ligands that are already in use worldwide. The intra- and interassay variation of receptor determination was similar for all 3 ligands. Receptor levels were analyzed with each of the 3 progestins in control cytosols and in 26 mammary carcinoma samples. A good correlation between receptor levels was found although the values of ORG-2058 were somewhat lower, but not significantly. This resulted in a lower proportion of receptor positive samples for ORG-2058 (11/26) compared to R-5020 (13/26) and RU-27987 (14/26). The affinity to the progesterone and to the glucocorticoid receptor, as well as the precision of the Scatchard plot analysis were comparable for the 3 ligands tested. Intra- and interassay variation of receptor determination were also similar. We therefore conclude, that RU-27987 is a suitable ligand to determine progesterone receptor in mammary carcinoma.

Clinical experience with trimegestone as a new progestin in HRT.

Trimegestone (TMG) is a novel, 19-norpregnane progestin, which demonstrates endometrial selectivity with a reduced progestin-related side effect profile when compared to several other currently marketed progestins. TMG has been studied in combination with 17beta-estradiol (17beta-E2) and conjugated equine estrogens (CEE). TMG-containing HRT agents were effective in relieving vasomotor symptoms and providing protection from endometrial hyperplasia with < or =1% hyperplasia. In clinical trials with sequential regimens, TMG provided predictable withdrawal bleeding associated with a low incidence of irregular and prolonged bleeding. Clinical studies of continuous combined regimens of estrogen/TMG combinations demonstrated high levels of amenorrhea. Both 17beta-E2 and CEE/TMG combinations have shown improved bone mineral density and quality-of-life assessments. Both continuous combined and sequential regimens of 17beta-E2/TMG and CEE/TMG have a favorable clinical profile. TMG provides an important new option for the treatment of postmenopausal symptoms and the prevention of osteoporosis.

The preclinical biology of a new potent and selective progestin: trimegestone.

Trimegestone (TMG) is a 19-norpregnane progestin being developed, in combination with an estrogen, for the treatment of postmenopausal symptoms. TMG binds to the human progesterone receptor with an affinity greater than medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). In contrast, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor. Compared to other progestins, TMG demonstrates an improved separation of its PR affinity from its affinity to other classical steroid hormone receptors. In vivo, TMG has potent progestin activity. For example, TMG produces glandular differentiation of the uterine endometrium in rabbits and is about 30 and 60 times more potent than MPA and NET, respectively. In the rat, TMG maintains pregnancy, induces deciduoma formation, inhibits ovulation and has uterine anti-estrogenic activity. With respect to these endpoints, TMG appears to be more potent and selective on uterine epithelial responses than other classical progestin responses. In vivo, TMG does not have significant androgenic, glucocorticoid, anti-glucocorticoid or mineralocorticoid activity but does have anti-mineralocorticoid activity and modest anti-androgenic effects. This overall profile is qualitatively similar to progesterone. When TMG is administered chronically, it antagonizes the effect of estradiol on the uterus but does not antagonize the beneficial bone sparing activity of estradiol. In rat studies evaluating CNS GABAA receptor modulatory activity, TMG is less active on this likely undesirable endpoint than progesterone and norethindrone acetate, which may translate into fewer mood-related side effects. The results indicate that TMG is a potent and selective progestin with a preclinical profile well suited for hormone replacement therapy.

In vitro characterization of trimegestone: a new potent and selective progestin.

Trimegestone (TMG) is a novel 19-norpregnane progestin under development for hormone replacement therapy and oral contraception. The objective of the current study was to characterize the potency and steroid receptor selectivity of TMG in several in vitro assays and to compare its activity to that of medroxyprogesterone acetate (MPA). TMG and MPA had a similar competitive binding affinity for human and rabbit progesterone receptor (PR). However, TMG had a significantly higher affinity for rat PR (IC(50) = 3.3 nM) than MPA (IC(50) = 53.3 nM). In T47D cells, both compounds increased alkaline phosphatase activity and cell proliferation with comparable potencies (EC(50s) of 0.1 nM and of 0.02 nM, respectively). To further characterize the progestational activity and steroid receptor selectivity, we established an immortalized human endometrial stromal cell line (HESC-T). This cell line lacks endogenous estrogen receptor (ER) and PR but does have functional glucocorticoid receptors (GR). When ER is transiently expressed in the cells, 17beta-estradiol (E(2)) induces PR, allowing the study of PR-regulated genes. In HESC-T cells expressing exogenous ER, and therefore PR, both TMG and MPA increased HRE-tk-luciferase activity tenfold with an EC(50) of 0.2 nM. In HESC-T cells without exogenous ER, and therefore no PR, TMG did not induce HRE-tk-luciferase activity, whereas MPA induced the reporter activity with an EC(50) of about 10 nM. This MPA-induced reporter activity is believed to be mediated through GR. The steroid receptor selectivity of TMG was further evaluated using the HRE-tk-luciferase assay in the human lung carcinoma cell line A549, which contains GR but no PR. In these cells TMG had no effect on luciferase activity, whereas MPA increased the reporter activity in a dose-dependent manner with an EC(50) of approximately 30 nM. Furthermore, HRE-tk-luciferase assay in mouse fibroblast cell line L929, which expresses androgen receptor (AR) but no PR, showed that TMG had weak antiandrogenic activity whereas MPA had androgenic activity. In summary, data from several in vitro assays demonstrate that TMG is a potent progestin with a better receptor selectivity profile than MPA.

In vitro labeling of gonadal steroid hormone receptors in brain tissue sections.

Autoradiographic methods have been developed for measurement of gonadal steroid receptors in situ in brain tissue sections. Based on principles established previously for estrogen receptors in the rat brain using a 125I-labeled ligand, procedures have been developed for in vitro labeling of estrogen, androgen, and progestin receptors with commercially available tritiated ligands. Addition of protamine sulfate to the incubation buffer precipitates the receptors in situ in the tissue sections, allowing them to be detected autoradiographically after incubation with labeled steroid and subsequent washing to remove unbound and nonspecifically bound ligand. Occupied and unoccupied estrogen receptors can be measured selectively using appropriately modified incubation conditions. In the case of androgen and progestin receptors, unoccupied receptors are readily detected by in vitro labeling of tissue sections, but occupied receptors do not appear to label efficiently. Preliminary data suggest that these methods should be equally applicable to a variety of laboratory animals, including the rat, mouse, guinea pig, and monkey.

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.

Physical evaluation of a new patch made of a progestomimetic in a silicone matrix.

The adhesion of a new Transdermal Therapeutic System (TTS) made of silicone and loaded with a progestomimetic drug was characterised. The goal of this study was to use well-known methods or to adapt them to collect representative data. Individually, methods such as surface tension, peel test and rheology are already widely used. Results show that the choice of a substrate for peel tests can be made in the light of surface tension data and that polymers like poly(tetrafluoroethylene) (PTFE) are good alternatives to skin. Peeling characterisations are made a function of thickness of films, drug content in active, conditions of preparation and conditions of use such as pressure. Dynamic rheology is more difficult to link to other methods as it mainly reflects internal phenomena and properties that arise in the bulk, as opposed on its surface. Master curves enable results to be used more easily, but the theories to interpret the data are still not powerful enough to replace peel testing.

A study of the adhesive-skin interface: correlation between adhesion and passage of a drug.

The phenomena taking place at the patch-skin interface, in particular the adhesion of a pressure sensitive adhesive (PSA) film loaded with drug and the partition of the drug between the patch and the skin were correlated. The kinetics of adhesion as well as those of drug passage were studied in detail. Adhesion data were collected from peel test either on skin or on a polymer model. Passage of the drug was studied in a simple system composed of PSA film stuck on skin. In some experiments the film was left on the skin throughout the experiment; in others, it was periodically removed and stuck on again to keep the adhesion force constant during the whole of the experiment. We observed a rapid increase of the drug content in the skin until a plateau was reached. One adhesion for the whole experiment or several adhesions gave a similar curve. The main difference was the rate of increase of skin drug content and the value of the plateau. Different hypotheses concerning the relationship between the adhesion of this PSA and changes in the flux of drug have been put forward. However, it is difficult to extrapolate from this model to the in vivo situation because of variation both between individuals and with time.