Estrogen activity and novel tissue selectivity of Delta(8,9)-dehydroestrone sulfate in postmenopausal women

Estrogen activity and novel tissue selectivity of Delta(8,9)-dehydroestrone sulfate in postmenopausal women

Autor Baracat, Edmund Chada Autor UNIFESP Google Scholar
Haidar, R. Autor UNIFESP Google Scholar
Lopez, F. J. Google Scholar
Pickar, J. Google Scholar
Dey, M. Google Scholar
Negro-Vilar, A. Google Scholar
Instituição Wyeth Ayerst Labs Inc
Universidade Federal de São Paulo (UNIFESP)
Resumo Recent basic and clinical advances have consolidated the concept of tissue-selective estrogens, i.e. molecules that express different degrees of partial agonist, full agonist or antagonist activity in different tissues or cells. Delta(8,9)-Dehydroestrone sulfate (Delta(8,9)-DHES) is a conjugated estrogen and a component of conjugated equine estrogens (CEE). It is metabolized in the human in at least a 1:1 ratio to its 17 beta form, 17 beta-Delta(8,9)-DHES. To evaluate its activity in different clinical and biochemical parameters, a clinical research study was conducted with Delta(8,9)-DHES and estrone sulfate as a comparator in postmenopausal women. Delta(8,9)-DHES was given orally at a daily dose of 0.125 mg for 12 weeks in a group of 10 women. Two additional groups of women received either estrone sulfate alone (1.25 mg/day) or the combination of Delta(8,9)-DHES and estrone sulfate at the previously specified doses. A significant and consistent suppression of hot flushes (number, severity, and total score) was observed with Delta(8,9)-DHES, reaching more than 95% suppression in all parameters of vasomotor symptoms. This level of activity was equal to that obtained with the much higher dose of estrone sulfate, and it was sustained for the duration of the treatment period (12 weeks). Measurements of a bone resorption marker. i.e. urinary excretion of N-telopeptide, demonstrated that Delta(8,9)-DHES at 8 weeks produced a degree of suppression (40%) similar to that observed with the higher dose of estrone sulfate. Gonadotropin secretion (FSH and LH) was significantly suppressed in women receiving Delta(8,9)-DHES, similar to that observed with estrone sulfate alone or with the combination of the two. Other parameters, such as total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol were not modified significantly, whereas serum globulins (sex hormone-binding globulin and corticosteroid-binding globulin) showed only marginal increases after Delta(8,9)-DHES administration.Taken together with preclinical data, it is found that Delta(8,9)-DHES is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine (gonadotropin and PRL) and bone preservation parameters, whereas displaying little or no efficacy, at the dose tested, on other peripheral parameters normally affected by estrogens, Collectively, this information supports the concept that Delta(8,9)-DHES is an integral component of GEE, with distinct tissue selectivity contributing to the CEE's overall clinical activity, and places this estrogen as a distinct member of a novel class of centrally active molecules with unique peripheral tissue selectivity.
Idioma Inglês
Data de publicação 1999-06-01
Publicado em Journal of Clinical Endocrinology & Metabolism. Washington: Endocrine Soc, v. 84, n. 6, p. 2020-2027, 1999.
ISSN 0021-972X (Sherpa/Romeo, fator de impacto)
Publicador Endocrine Soc
Extensão 2020-2027
Fonte http://dx.doi.org/10.1210/jcem.84.6.5800
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000080674000054
Endereço permanente http://repositorio.unifesp.br/handle/11600/26085

Exibir registro completo




Arquivo

Arquivo Tamanho Formato Visualização

Não existem arquivos associados a este item.

Este item está nas seguintes coleções

Buscar


Navegar

Minha conta