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At least 55 records · Page 3Linked to original sources
PubMed1982

Dehydroepiandrosterone synthesis by the fetal foal and its importance as an oestrogen precursor.

The gonads of the fetal horse were found to be relatively devoid of 3 beta-hydroxysteroid dehydrogenase and other enzymes which metabolize dehydroepiandrosterone (DHA). In short-term in-vitro incubation experiments fetal liver converted DHA to the potential equilin precursor, 7 alpha-hydroxy DHA. DHA was converted to oestrone when incubated with extracts of horse placenta but 7 alpha-hydroxy DHA was not converted to equilin. Levels of DHA measured in peripheral blood of mares throughout pregnancy paralleled those of equilin and oestrone, and DHA concentrations fell rapidly after fetal gonadectomy, as did those of equilin and oestrone. Administration of [4-(14)C]-DHA and [7-3H]DHA to the fetus resulted in the incorporation of both 14C and 3H into maternal urinary oestrone but neither isotope was present in urinary equilin. These findings confirm the role of fetal DHA as a precursor of oestrone, but do not support the previously suggested role of the fetal liver in the synthesis of equilin. They are, however, compatible with the hypothesis that equilin is formed via a pathway which diverges from the terpenoid steroid synthetic route before DHA.

Animals↗
PubMed1994

Pharmacokinetics of 17 beta-dihydroequilin sulfate and 17 beta-dihydroequilin in normal postmenopausal women.

The MCRs of 17 beta-dihydroequilin sulfate and 17 beta-dihydroequilin were determined in normal postmenopausal women by single iv injection of either 17 beta-[3H]dihydroequilin sulfate ([3H]17 beta-EqS) or 17 beta-[3H]dihydroequilin ([3H]17 beta-Eq). After the administration of [3H]17 beta-EqS, blood was drawn at various time intervals, and the plasma obtained was fractionated into the unconjugated, sulfate, and glucuronide fractions. The bulk of radioactivity was present in the sulfate fraction, and from this [3H]17 beta-EqS, [3H]equilin sulfate, [3H]equilenin sulfate, and 17 beta-[3H]dihydroequilenin sulfate were isolated and purified, and their concentrations were measured. The disappearance of [3H]17 beta-EqS from plasma can be described as a function of two exponentials. The half-life of the initial fast component was 5 +/- 0.2 min; this component represents the distribution and transfer from a space, with a mean volume (V1) of 6 +/- 0.5 L. The value for the rate constant (k) of total removal from this space was 300 +/- 20 U/day, of which 35 +/- 2% was irreversible. The mean half-life of the slower component of 17 beta-EqS was 147 +/- 15 min, and the mean MCR was 376 +/- 93 L/day.m2. Similarly, after the administration of [3H]17 beta-Eq, the disappearance of radioactivity as 17 beta-Eq from plasma also had two components. The half-lives of the fast and slow component were 5.5 +/- 0.8 and 45 +/- 2.0 min, respectively. The MCR of 17 beta-Eq was 1252 +/- 103 L/day.m2. From both series of experiments, unconjugated and sulfate-conjugated equilin, equilenin, and 17 beta-dihydroequilenin were isolated and purified, and their concentrations were measured. No 17 alpha-reduced metabolites were detected. These results indicate that 17 beta-EqS is cleared twice as fast as equilin sulfate (MCR, 176 L/day.m2), whereas the more potent estrogen 17 beta-Eq is cleared 2 times slower than equilin. The slower elimination and greater estrogenic activity of 17 beta-Eq support the hypothesis that the major in vivo activity of equilin sulfate present in conjugated equine estrogen preparations is expressed via its metabolites 17 beta-EqS and 17 beta-Eq.

Equilin↗
PubMed1996

The effect of various oestrogens and progestogens on the susceptibility of low density lipoproteins to oxidation in vitro.

OBJECTIVE: To investigate the effect of different oestrogens and progestogens, at various concentrations, on the oxidation of low density lipoproteins (LDL) in vitro. METHODS: Oestradiol, oestrone, oestriol and equilin, as well as medroxyprogesterone acetate, norgestrel and norethisterone, were added to isolated male LDL, before it was oxidised in the presence of copper ions at 37 degrees C. The oxidation process was monitored spectrophotometrically by the production of conjugated dienes. The lag time to oxidation and the maximum rate of propagation of the reaction were used as measures of the resistance and susceptibility of the LDL to oxidation respectively. RESULTS: The lag time was increased from 43.7 +/- 1.5 min (mean +/- SEM) for LDL without any added hormone, to 81.2 +/- 1.0 min by 1 microM oestradiol (P < 0.01), 77.9 +/- 4.6 min by 1 microM oestrone (P < 0.01), 67.6 +/- 6.2 min by 1 microM equilin (P < 0.01), and 51.8 +/- 2.8 min by 1 microM oestriol (P < 0.05). The maximum rate of propagation of the reaction was decreased from 0.23 +/- 0.01 nmol conjugated dienes/mg LDL-protein/min (mean +/- SEM) (control LDL) to 0.14 +/- 0.006 nmol/mg/min by oestradiol (P < 0.01), 0.15 +/- 0.009nmol/mg/min by oestrone (P < 0.01), 0.17 +/- 0.012 nmol/mg/min by equilin (P < 0.01) and 0.19 +/- 0.014 nmol/mg/min (P < 0.05) by oestriol. The progestogens alone had no antioxidant effect, nor did their addition to the oestrogens influence their antioxidant activity. CONCLUSIONS: These results demonstrate that all oestrogens investigated have an inhibitory effect on LDL oxidation in vitro. The magnitude of this effect varied, being of the order oestradiol > oestrone > equilin > oestriol.

Dose-Response Relationship, Drug↗
PubMed1998

Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism.

Conjugated equine estrogens (Premarin), are used extensively for estrogen replacement therapy and prevention of osteoporosis and cardiovascular disease in postmenopausal women. Premarin contains at least 10 estrogens that are the sulfate esters of the ring B saturated estrogens: estrone, 17beta-estradiol, 17alpha-estradiol, and the ring B unsaturated estrogens: equilin, 17beta-dihydroequilin, 17alpha-dihydroequilin, equilenin, 17beta-dihydroequilenin, 17alpha-dihydroequilenin, and delta-8-estrone. Bioassays and estrogen receptor binding studies indicate that all 10 estrogens are biologically active. Moreover, individual components, such as equilin sulfate, delta-8-estrone sulfate, 17beta-dihydroequilin sulfate and estrone sulfate, have potent estrogenic effects. Estrogen sulfates can be absorbed directly from the gastrointestinal tract; however, hydrolysis of the sulfates also occurs in the gastrointestinal tract, and the unconjugated estrogens formed are readily absorbed. After absorption, these estrogens are sulfated rapidly and circulate in this form. The pharmacokinetics of these estrogens indicate that the unconjugated estrogens are cleared from the circulation at a faster rate than their sulfate ester forms. In postmenopausal women, the 17-keto derivatives of these estrogens are metabolized to the more potent 17beta-reduced products. The extent of this activation is nearly 10 times higher with some ring B unsaturated estrogens. The 17beta-reduced metabolites are cleared from the blood at a slower rate than their corresponding 17-keto derivatives. In the human endometrium, equilin is metabolized to 2-hydroxy and 4-hydroxy equilin, with 2-hydroxylation being predominant. In contrast, 2-hydroxy and 4-hydroxy estradiol are formed in equal amounts. Similarly, 16alpha-hydroxylation occurs with both types of estrogens; however, with the ring B saturated estrogens, the 17-keto steroid 16alpha-hydroxy estrone was the major urinary metabolite, whereas with the ring B unsaturated estrogens, the 17beta-reduced steroids, such as 16alpha-hydroxy-17beta-dihydroequilin and 16alpha-hydroxy-17beta-dihydroequilenin, were the major metabolites. This difference in metabolism may be important as it has been suggested that 16alpha-hydroxy estrone (alpha-ketol structure) can form covalent adducts with macromolecules and that it may be oncogenic. These types of interactions will not occur with the 16alpha-hydroxylated-17beta-reduced metabolites of ring B unsaturated estrogens. Since all of the estrogens present in Premarin have estrogenic activity, the pharmacological effects of Premarin are a result of the sum of these individual activities. Therefore, preparations lacking some of these important components may not offer the same degree of beneficial effects as Premarin.

Animals↗
PubMed1983

Biosynthesis of 3 beta-hydroxy-5,7-pregnadien-20-one by the horse fetal gonad.

The production of equilin and the other ring B-unsaturated estrogens by the pregnant mare is anomalous in that they are biosynthesised by a cholesterol-independent pathway. Fetal horse gonads were incubated with tritiated sodium acetate and radiochemically pure 3 beta-hydroxy-5,7-pregnadien-20-one and 3 beta-hydroxy-5,7-androstadien-17-one were isolated. A fetal gonad--placental system is proposed for equilin production, 3 beta-hydroxy-5,7-pregnadien-20-one being a precursor for 3 beta-hydroxy-5,7-androstadien-17-one in the fetal gonad and the latter being the precursor of equilin in the placenta. The nature of the possible precursor of 3 beta-hydroxy-5,7-pregnadien-20-one is discussed.

Animals↗
PubMed1996

Superior and distinct antioxidant effects of selected estrogen metabolites on lipid peroxidation.

The effect of the estrogen metabolites, 4-hydroxyestrone and 17alpha-dihydroequilin (metabolites of estradiol-17beta and equilin, respectively), were examined for antioxidant effects on plasma and lipoprotein lipid peroxidation . Lipid peroxidation was evaluated by products of both fatty acid (thiobarbituric acid-reactive substances [TBARS]) and cholesterol (oxysterols) oxidation from lipoproteins or whole plasma. Although all estrogens significantly reduced lipid peroxidation, 4-hydroxyestrone was far more potent than either equilin or 17alpha-dihydroequilin in inhibiting TBARS formation in lipoproteins induced by Cu2+. Similar effects were also noted on TBARS formation in THP-l macrophages in culture. However, 17alpha-dihydroequilin (along with equilin) strongly inhibited oxysterol formation, whereas 4-hydroxyestrone was ineffective. These studies suggest that different estrogens might act preferentially on distinct lipid substrates in exhibiting antioxidant effects.

Antioxidants↗
PubMed2003

Equine estrogens differentially prevent neuronal cell death induced by glutamate.

OBJECTIVE: In the present study, neuronal PC12 cells and hippocampal HT22 cells maintained in culture were used to test the neuroprotective effect of equine estrogens estrone, 17beta-estradiol, 17alpha-estradiol, equilin, 17beta-dihydroequilin, 17alpha-dihydroequilin, equilenin, 17beta-dihydroequilenin, 17alpha-dihydroequilenin, Delta(8)-estrone(,) and Delta(8),17beta-estradiol against glutamate toxicity. METHODS: The HT22 and PC12 cells were grown in Dulbecco modified Eagle medium supplemented with 5% horse serum, 10% fetal bovine serum, and 10 mM HEPES. The undifferentiated PC12 cells were plated on collagen-coated, 96-well plastic plates at 10,000 cells per well, and the HT22 cells were plated on uncoated 96-well plates at 2500 cells per well. Twenty-four hours after plating, various concentrations of estrogens (0.1-40 microM) and glutamate (1-10 mM) were added in a total volume of 100 microL. After 24 hours, cell viability was determined using the MTS cell proliferation assay. Results were verified in some experiments by using the lactate dehydrogenase cytotoxicity assay. RESULTS: The results indicate that cell toxicity in both cell lines was directly proportional to the concentration of glutamate. The lowest dose of glutamate that reduced cell viability by 50% under these conditions was 1.8 mM for HT22 cells and 3 mM for PC12 cells. All estrogens tested were neuroprotective against glutamate-induced cell death in a typical dose-related manner. However, these estrogens differed extensively with respect to their neuroprotective potencies. In both cell lines, the Delta(8)-ring B unsaturated estrogens were the most neuroprotective, whereas the classic estrogens 17beta-estradiol, estrone, and 17alpha-estradiol were the least potent. The order of potency was Delta(8),17beta-estradiol > Delta(8)-estrone > 17beta-dihydroequilenin > 17alpha-dihydroequilenin > equilenin > 17beta-dihydroequilin = equilin > 17alpha-dihydroequilin > 17beta-estradiol > estrone > 17alpha-estradiol in PC12 cells and Delta(8),17beta-estradiol > Delta(8)-estrone > equilenin = 17beta-dihydroequilenin > 17beta-dihydroequilin > equilin > 17alpha-dihydroequilenin > 17alpha-dihydroequilin > 17alpha-estradiol = 17beta-estradiol > estrone in HT22 cells. CONCLUSIONS: Our data indicate that the neurotoxic effects of glutamate can be inhibited differentially by various equine estrogens. The less estrogenic (uterotropic) Delta(8) estrogens were the most effective neuroprotectors, and further chemical modifications of these estrogens may provide compounds that are useful for preventing neurodegenerative diseases in both women and men.

Animals↗
PubMed1999

Synthesis of the equine estrogen metabolites 2-hydroxyequilin and 2-hydroxyequilenin.

Equilin and equilenin make up approximately 20% of Premarin which is currently the most popular estrogen replacement therapy. Although there are numerous health benefits of estrogen replacement therapy, there are concerns over the link between estrogen replacement therapy and breast and endometrial cancer risk. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols which are further oxidized to electrophilic/redox active o-quinones which have the potential to both initiate and promote the carcinogenic process. In this investigation, we have synthesized potential metabolites of equilin and equilenin, 2-hydroxyequilin and 2-hydroxyequilenin, respectively, as well as their methyl ether metabolites. These compounds were synthesized from commercially available optically pure equilin via a practical and efficient approach; five steps gave 2-methoxyequilin from which 2-hydroxyequilin was prepared by BBr3-catalyzed demethylation in one step. Similarly, treating 2-methoxyequilin with SeO2 followed by demethylation with BBr3 produced 2-hydroxyequilenin. The structures of the catechols as well as those of their methoxy ethers were unambiguously characterized by one-dimensional and two-dimensional NMR experiments, including 1H, 13C, APT, COSY, HMBC, and HMQC as well as mass spectrometry.

Animals↗
PubMed2002

Evaluation of single- and multiple-dose pharmacokinetics of synthetic conjugated estrogens, A (Cenestin) tablets: a slow-release estrogen replacement product.

A multiple-dose, placebo-controlled, randomized pharmacokinetic study was performed in 15 early (i.e., 1-3 years) postmenopausal women to evaluate the single and steady-state pharmacokinetics of 0.625 mg Cenestin (Synthetic Conjugated Estrogens, A) tablets, administered once daily for 90 days. Plasma concentration-time profiles for both total (conjugated and unconjugated) estrone and equilin, two major estrogens in Cenestin, were nearly superimposable between Day 1 (single dose) and Day 90 (multiple dose), indicating equivalent drug exposure from one dose to the next. For total estrone, the mean estimates of Cmax and AUC0-24 were 2.5 ng/ml and 35.0 ng x h/ml for Day 1 and 3.0 ng/ml and 39.8 ng x h/ml for Day 90, respectively. Similarly, Cmax and AUC0-24 mean values for total equilin were 1.4 ng/ml and 17.4 ng x h/ml after Day 1 and 1.5 ng/ml and 17.3 ng x h/ml after Day 90, respectively. The mean tmax value for total estrone was 8.3 hours on Day 1 and 8.6 hours on Day 90, indicating a slower rate of absorption. The average estimate for observed drug accumulation index for the 24-hour dosing interval was calculated to be 1.1 for total estrone and 1.0 for total equilin. These data, taken together, indicate a slow and steady rate of absorption, minimal drug accumulation at steady state, and consistent drug exposure between Cenestin doses.

Adult↗