Biomedical subjects

N J MacLusky

Publications and source records attributed to N J MacLusky.

147 records · Page 9Linked to original sources

PubMedDate not supplied

Rationale for estrogen with interrupted progestin as a new low-dose hormonal replacement therapy.

OBJECTIVE: This review outlines the basic principles of a novel interrupted progestin hormone replacement therapy (HRT) regimen in which estrogen is given continuously but the progestin is administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent receptor down-regulation and allow estrogen to increase estrogen and progestin sensitivity during the progestin-free periods. METHODS: The reasons for poor patient acceptance of HRT are reviewed. The association of HRT with breast and endometrial cancer is discussed, as are the potential benefits of HRT on the skeleton and the cardiovascular system. Basic research studies in the rat are described that provide supporting evidence for the interrupted progestin regimen. Clinically, we review a pilot study examining symptom control, bleeding rates, and safety of the interrupted progestin regimen as well as preliminary results of the usefulness of this regimen for add-back therapy in GnRH agonist-treated patients. RESULTS: Estrogen and progestin receptor measurements in the rat uterus demonstrate a clear up- and down-regulation in response to estrogen and interrupted progestin but not to the continuous administration of estrogen and progestin or estrogen alone. In addition, we found a significant beneficial effect of a low-dose interrupted HRT regimen on bone mineral content and density in an aged rat model of osteopenia, compared with continuous estrogen and progestin or estrogen alone. These results support the hypothesis that the interrupted progestin HRT increases tissue sensitivity to both estrogen and progestin. Clinical studies demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. CONCLUSION: The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen-responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance of this new regimen compared to continuous combined HRT.

Animals↗

PubMedDate not supplied

Hormonal regulation of K+-channel messenger RNA in rat myometrium during oestrus cycle and in pregnancy.

The dramatic enhancement of smooth-muscle excitability in the uterus which occurs at oestrus and at term in pregnant rats is closely related to increased blood oestrogen concentrations. How oestrogen alters the electrical properties of myometrial cells is unclear, although electrical coupling between cells has been shown to increase. Many examples are known of changes in cellular excitability involving modification of existing ion channels by second-messenger pathways. Steroid hormones, in contrast, are generally thought to influence cellular processes mainly through effects on gene expression, inducing the synthesis of new proteins. Previous work, using an oocyte translation system, has shown that a very slowly activating, voltage-dependent K+ current can be expressed from the poly(A)+ RNA of oestrogen-treated rat uteri. We report here that the messenger RNA species producing this channel is rapidly and reversibly induced in the presence of oestrogen, as shown by the appearance and disappearance of this mRNA during the oestrous cycle, its emergence at the end of pregnancy, and its presence or absence following hormonal treatments. These results suggest that oestrogen controls the expression of a voltage-dependent ion channel in uterine smooth muscle cells.

Animals↗

PubMedDate not supplied

Hormonal interactions in the effects of halogenated aromatic hydrocarbons on the developing brain.

Halogenated arylhydrocarbons (HAHs) exert a wide range of effects on the developing brain. These effects result in altered patterns of neuroendocrine function and behavior in adulthood, as well as changes in cognitive function. The underlying mechanisms have not yet been clearly defined. This paper briefly reviews the effects of HAHs on brain development, and proposes the hypothesis that interactions between different hormone-sensitive systems may contribute to the broad spectrum of responses observed after fetal or early postnatal HAH exposure. Physiological interactions between the effects of sex steroids, corticosteroids, and thyroid hormone are known to influence the development of the central nervous system (CNS). Since the biosynthesis and/or action of each of these hormones is sensitive to developmental HAH exposure, it is suggested that convergent effects of HAHs on different endocrine pathways may underlie some of the disruptive effects of these chemicals on CNS differentiation. Data are presented indicating that the disruptive effects of low dose dioxin exposure on sexual differentiation of the rat brain are probably not mediated through blockade of estrogen responses, but may instead involve subtle developmental changes in other endocrine systems, perhaps also affecting the feedback control of adrenocortical function. The potential for interactive endocrine effects illustrates the need for a fuller understanding of the range of biological activities of HAHs in the brain, so that the potential risks of low dose developmental exposure to these environmental toxicants can be predicted with greater certainty.

Adrenal Cortex Hormones↗