4-hydroxyestradiol and Body-Weight

Animal studies have shown that endogenous estrogens such as 17β-estradiol (E

Topics: Adipose Tissue; Animals; Body Weight; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Eating; Estrogens, Catechol; Female; Gene Expression Regulation, Enzymologic; Leptin; Liver; Liver X Receptors; Methylation; Ovariectomy; PPAR gamma; Rats; Rats, Sprague-Dawley

Endogenous estrogen metabolism may play an important role in the pathogenesis of hormone-related cancers, most notably breast cancer. Despite the importance of estrogen metabolism, little is known about estrogen metabolite profiles during different phases of the menstrual cycle. This study was performed to evaluate the effects of the menstrual cycle on endogenous estrogen metabolism. Twenty-four-hour urine samples were collected daily during 4 precisely defined phases of the menstrual cycle (early follicular, midfollicular, periovulatory, and midluteal phases) from 6 healthy premenopausal women. Urine samples were analyzed for 15 endogenous estrogens and their metabolites by an ion exchange chromatography and the capillary gas chromatography-mass spectrometry method. The patterns of urinary estrogen metabolites (including potentially genotoxic 16alpha-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone) followed those of plasma estradiol and estrone, showing significant increases in the periovulatory and midluteal phases. Compared to the early and midfollicular phases, the ratios of 2-hydroxyestrogens/16alpha-hydroxyestrogens and 2-hydroxyestrogens/4-hydroxyestrogens were significantly increased during the periovulatory and midluteal phases (by 28% and 72%, respectively; P < 0.05), suggesting that estrogen metabolism is significantly affected by menstrual cycle phase. These data indicate that menstrual cycle phase must be considered in studies of estrogen metabolism in premenopausal women.

Topics: Adult; Body Weight; Diet; Estradiol; Estrogens; Estrogens, Catechol; Estrone; Female; Follicular Phase; Gas Chromatography-Mass Spectrometry; Humans; Hydroxyestrones; Luteal Phase; Menstruation; Ovulation

17 beta-Estradiol (E2) has long been known for protecting against coronary heart disease by lowering cholesterol levels in premenopausal women. A recent study in our laboratory suggested that two hydroxylated metabolites of E2 possess similar hypocholesterolemic effects in male rats. This effect has been further investigated with additional estrogen metabolites in ovariectomized rats with a view toward mimicking the true postmenopausal situation in humans. Their effects in reproductive tissues were also evaluated histologically. Fundamentally, the following issues were addressed: (1) Do oxidized metabolites of estradiol lower total cholesterol levels? (2) Can a hypocholesterolemic effect be achieved without eliciting estrogenic activities on reproductive tissues? The results of this investigation showed that a number of oxygenated metabolites of estradiol can lower cholesterol levels. Among them, 4-hydroxyestradiol (4-OHE2) produced a striking hypocholesterolemic effect and a substantial uterotropic effect. 2-Hydroxyestradiol (2-OHE2), 2-methoxyestradiol (2-meoE2) and 2-methoxyestrone (2-meoE1) produced a significant decrease in cholesterol levels at doses that did not produce significant uterotropic effects.

Topics: Animals; Anticholesteremic Agents; Body Weight; Cholesterol; Estradiol; Estrogens, Catechol; Female; Ovariectomy; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Uterus

Osmotic minipumps containing low doses of either 4-hydroxyoestradiol or 2-hydroxyoestradiol2) were sc implanted for 152 h (6 1/3 day) into immature male and female rats. At the end of the test period the animals were killed and the uterine weight, the vaginal opening, the gonadotrophin serum levels and the gonadal weight monitored. The following results were obtained: 1) a significant increase in the uterine weight and a consistent vaginal opening were observed after 4-hydroxyoestradiol but not after 2-hydroxyoestradiol treatment, 2) LH-levels increased after 2-hydroxyestradiol but not after 4-hydroxyoestradiol; the increase was, however, not significant, 3) FSH-levels and gonadal weights were lowered by 4-hydroxyoestradiol treatment in male animals only; 2-hydroxyoestradiol had not effect on FSH-levels in both sexes, 4) in no instance an antioestrogenic effect of either catecholoestrogen was observed. It is concluded that 4-hydroxyoestrogens - using the above paradigm - have a significant importance on uterine growth and vaginal opening but (on day 6) no role of LH-release, whereas 2-hydroxyoestrogens may increase LH levels (on day 6) but are nearly ineffective with respect to peripheral parameters.

Topics: Animals; Body Weight; Drug Implants; Estradiol; Estrogens, Catechol; Female; Follicle Stimulating Hormone; Luteinizing Hormone; Male; Organ Size; Rats; Testis; Uterus; Vagina

4-Hydroxyestradiol-17 beta and 4-hydroxyestradiol-17 alpha (5 or 20 microgram/d) were continuously s.c. infused for 3 days into ovariectomized adult rats. The serum levels of either epimer were virtually identical when the same dose was administered. 4-Hydroxyestradiol-17 beta significantly altered body and uterus weight and LH serum levels (negative and positive effects) at both doses tested. 4-Hydroxyestradiol-17 alpha showed no effects even at the 20 microgram/d dose. As both epimers have similar affinities for catechol O-methyltransferase, but their potencies regarding effects on lH serum levels differ markedly, it is concluded that the interaction of catecholestrogens with this enzyme is not essential for their effects on LH release.

Topics: Animals; Body Weight; Estradiol; Estrogens, Catechol; Female; Luteinizing Hormone; Organ Size; Rats; Structure-Activity Relationship; Uterus