Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to evaluate the long-term effect (6 months) of the luteinizing hormone-releasing hormone (LH-RH) agonist buserelin on pituitary and ovarian function in a group of 14 patients presenting with the polycystic ovarian (PCO) syndrome. Buserelin was given subcutaneously 200 micrograms three times daily for the first 7 days followed by 500 micrograms once daily. Blood samples were taken weekly for the first month and then every month for radioimmunoassay of LH, FSH and sex steroids. While LH levels were stimulated during the first 2 weeks and then declined towards baseline, serum FSH levels were reduced after only 1 week (P less than 0.05). Serum oestradiol levels were maximally suppressed to the menopausal range after 1 month and testosterone levels were also significantly inhibited (P less than 0.05) after 2 weeks of therapy. Dehydroepiandrosterone (DHEA) sulphate did not show any significant change while 17-hydroxyprogesterone was suppressed after the first month of buserelin administration (P less than 0.01). The apparent divergent response of the gonadotrophins and the reduction of ovarian steroids in spite of lack of suppression of LH levels can be explained by the marked inhibition of the bioactivity of LH assessed by dispersed mouse Leydig cells assay. The clinical evaluation of hirsutism did not detect any change during the 6 month period. No patient had any menstrual bleeding or spotting after the sixth week of buserelin. The monthly incidence of hot flushes varied between 50 to 66%. This study shows that LH-RH agonist administration can selectively inhibit ovarian function and could be an interesting approach to evaluate the respective contribution of the ovary and adrenal on the pathophysiology of the polycystic ovarian disease. Polycystic ovarian (PCO) syndrome is characterized by tonic and exaggerated secretion of LH leading to an excessive stimulation of the ovarian stroma and an increased production of androgens (Yen et al., 1970; DeVane et al., 1975; Rebar et al., 1976). The androgen precursor delta 4 androstenedione is transformed in peripheral tissues into oestrone (Siiteri & MacDonald, 1973), thus maintaining the state of pituitary hypersensitivity and creating a positive feedback (Yen et al., 1976). The starting point of this vicious circle is still controversial; some argue for a hypothalamic abnormality (Vaitukaitis, 1983) while others support the peripheral origin of the hypersecretion of steroids (Reyniak, 1983). The importance of the adrenal contribution in this syndrome is still unclear.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ovarian suppression in polycystic ovarian disease during 6 month administration of a luteinizing hormone-releasing hormone (LH-RH) agonist. 313 52

For decades, hormone therapy (HT) has been the mainstay for managing menopausal symptoms. However, fear of breast cancer, as well as side-effects such as breast pain and return of vaginal bleeding, have made many women stop HT or refuse to take it. There is therefore a clear need for alternative treatments. Recent years have seen the development of hormonal agents with selective effects, such as tibolone. Tibolone has a unique mode of action and is described as a STEAR (Selective Tissue Estrogenic Activity Regulator). The main action of tibolone is mediated through two 3-hydroxy metabolites; small amounts of a third metabolite are also found in the circulation. In the brain, the effect is estrogenic and perhaps androgenic and, as such, tibolone relieves hot flushes and improves energy and sexual well-being. The uterus converts tibolone and its hydroxy metabolites into a Delta4 metabolite that has a progestogenic effect. In the breast, the metabolites of tibolone inhibit key enzymes that result in estrogen depletion within the breast itself. Clinically, tibolone does not stimulate the breast and it does not increase mammographic density. There are several key large, placebo-controlled international trials of tibolone currently underway, one of which (LIBERATE) aims to test the safety of tibolone (vs placebo) in women with a history of breast cancer who are suffering from climacteric symptoms.
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PMID:The need for tissue selective menopausal agents. 1611 52

Tibolone is used therapeutically as a hormone replacement agent and has beneficial effects on osteoporosis and hot flushes as well as libido in post-menopausal women without stimulatory effects in the breast and endometrium. The lack of effect in the endometrium is due in part to the tissue specific sulfation of tibolone and its active metabolites in endometrial tissues. Tibolone is metabolized into 3alpha-OH and 3beta-OH tibolone as well as the Delta4-isomer. Tibolone and the Delta4-isomer bind and activate progesterone and androgen receptors whereas 3alpha-OH and 3beta-OH tibolone activate the estrogen receptors. Human endometrium and Ishikawa endometrial adenocarcinoma cells express SULT1E1 that efficiently sulfates both 3-OH tibolone metabolites and has trace activity with tibolone but no activity with the Delta4-isomer. Treatment of Ishikawa cells with all four tibolone compounds resulted in the induction of SULT1E1 activity similar to the induction by progesterone. The induction of SULT1E1 was inhibited by RU486 indicating a role for the progesterone receptor. Sulfation of the tibolone compounds by Ishikawa cells and Ishikawa cells expressing physiological levels of SULT1E1 activity resulted in the sulfation of tibolone and the 3-OH metabolites but not Delta4-tibolone. These results indicate that the lack of endometrial stimulation involves induction of SULT1E1 and the selective sulfation and inactivation of the estrogenic 3-OH tibolones and interconversion of the tibolone metabolites to generate the progestagenic non-sulfated Delta4-isomer.
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PMID:Regulation of SULT1E1 expression in Ishikawa adenocarcinoma cells by tibolone. 1685 24