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.

[Effect of trimegestone on mammary gland of castrated rats]. / Efeito da trimegestona sobre o tecido mamário de ratas castradas.

PURPOSE: To evaluate the efect of trimegestone on the histological changes of the mammary tissue of castrated rats. METHODS: Forty-five virgin female Wistar rats were used after oophorectomy. Sixty days after surgery, with hypoestrogenisms confirmed, the experimental rats were randomly assigned to three groups of 15 animals each, when then the specific treatment for each group was started. The control group (C) and experimental groups 1 and 2 respectively received 0.9% saline solution, 17-beta-estradiol and 17-beta-estradiol in combination with trimegestone for 60 consecutive days. After the end of treatment , the inguinal mammary glands were removed, stained with hematoxylin and eosin (HE) for morphometry and examined by immunohistochemistry for the quantification of anti-PCNA antibody in the mammary tissue, followed by euthanasia. The morphometric parameters evaluated were: epithelium cell-proliferation, secretor activity and mammary stroma changes. There were nine deaths during the experiment. The variables were submitted to statistical analysis adopting the 0.05 level of significance. RESULTS: Histological changes were observed in 16/36 rats, mild epithelial hyperplasia in 13/36, moderate epithelial hyperplasia in 3/36, with no cases of severe epithelial hyperplasia. Stromal fibrosis was found in 10/36 and secretory activity in 5/36 rats. All morphometric variables were significant in the estrogen group compared to control (p=0.0361), although there were no difference between the group receiving combined treatment and the controls (p=0.405). The immunohistochemical analysis showed no difference between groups. CONCLUSIONS: The hormones administered to castrated rats, i.e., 17 beta-estradiol alone or in combination with trimegestone, increased the proliferation of breast cells, but this effect appeared to be lower in the combined treatment, the same occurring regarding fibrosis of the mammary stroma.

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.

Efeito da trimegestona sobre o tecido mamário de ratas castradas / Effect of trimegestone on mammary gland of castrated rats

OBJETIVO: Avaliar o efeito da trimegestona sobre a proliferação celular do tecido mamário de ratas castradas. MÉTODOS: Foram utilizadas 45 ratas adultas e virgens, da linhagem Wistar, submetidas à castração. Após o 60º dia da castração, confirmado o hipoestrogenismo, os animais foram divididos aleatoriamente em três grupos, conforme o tratamento proposto: controle (n=15) recebeu soro fisiológico 0,9 por cento; estrogênio (n=15) recebeu 17 beta-estradiol; e combinado (n=15) recebeu 17 beta-estradiol associado à trimegestona, todos por 60 dias consecutivos. Após o término do tratamento, procedeu-se a exérese das mamas inguinais, destinadas a análise morfométrica pela coloração de hematoxilina e eosina (HE) e imuno-histoquímica pela quantificação do anticorpo anti-PCNA no tecido mamário, seguido de eutanásia. Os parâmetros morfométricos avaliados foram: proliferação celular epitelial, atividade secretora e alteração do estroma mamário. Ocorreram nove óbitos durante o experimento. As variáveis foram submetidas à análise estatística adotando-se como significante p<0,05. RESULTADOS: Foram observadas alterações histológicas em 16/36 ratas, hiperplasia epitelial leve em 13/36, hiperplasia epitelial moderada em 3/36, não sendo encontrada hiperplasia epitelial severa. Encontrou-se fibrose no estroma em 10/36 e atividade secretora em 5/36 das ratas. Todas as variáveis do estudo morfométrico foram significantes comparando-se os grupos controle e estrogênio (p=0,03), e nenhuma foi significante na comparação dos grupos controle e combinado (p=0,4). A análise imuno-histoquímica não mostrou diferença entre os grupos. CONCLUSÃO: Os hormônios usados em ratas castradas aumentaram a proliferação de células mamárias, tanto o 17 beta-estradiol isolado quanto associado à trimegestona, porém este efeito parece ser menor quando se emprega a associação, o mesmo ocorrendo em relação à fibrose do estroma mamário.

PURPOSE: To evaluate the efect of trimegestone on the histological changes of the mammary tissue of castrated rats. METHODS: Forty-five virgin female Wistar rats were used after oophorectomy. Sixty days after surgery, with hypoestrogenisms confirmed, the experimental rats were randomly assigned to three groups of 15 animals each, when then the specific treatment for each group was started. The control group (C) and experimental groups 1 and 2 respectively received 0.9 percent saline solution, 17-beta-estradiol and 17-beta-estradiol in combination with trimegestone for 60 consecutive days. After the end of treatment , the inguinal mammary glands were removed, stained with hematoxylin and eosin (HE) for morphometry and examined by immunohistochemistry for the quantification of anti-PCNA antibody in the mammary tissue, followed by euthanasia. The morphometric parameters evaluated were: epithelium cell-proliferation, secretor activity and mammary stroma changes. There were nine deaths during the experiment. The variables were submitted to statistical analysis adopting the 0.05 level of significance. RESULTS:Histological changes were observed in 16/36 rats, mild epithelial hyperplasia in 13/36, moderate epithelial hyperplasia in 3/36, with no cases of severe epithelial hyperplasia. Stromal fibrosis was found in 10/36 and secretory activity in 5/36 rats. All morphometric variables were significant in the estrogen group compared to control (p=0.0361), although there were no difference between the group receiving combined treatment and the controls (p=0.405). The immunohistochemical analysis showed no difference between groups. CONCLUSIONS:The hormones administered to castrated rats, i.e., 17 beta-estradiol alone or in combination with trimegestone, increased the proliferation of breast cells, but this effect appeared to be lower in the combined treatment, the same occurring regarding fibrosis of the mammary stroma.

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.