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PubMed1992

Activation of human leukemia protein kinase C by tumor promoters and its inhibition by N-trifluoroacetyladriamycin-14-valerate (AD 32).

N-Trifluoroacetyladriamycin-14-valerate (AD 32), a lipophilic, DNA non-binding analog of Adriamycin (ADR), was found to be a potent inhibitor of the membrane-bound enzyme, protein kinase C (PKC). PKC was isolated and purified from human leukemia ML-1 cells, and the enzyme activity was shown to be activated by the tumor promoters 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol-12,13-dibutyrate (PDBu). AD 32, nevertheless, inhibited the activation of PKC by TPA or PDBu. The IC50 values for AD 32 inhibition of PKC activation were 0.85 microM for TPA and 1.25 microM for PDBu. Under the same assay conditions, ADR demonstrated much higher IC50 values: 550 microM for TPA and greater than 350 microM for PDBu. The inhibition of PKC by AD 32 was further shown to be competitive in nature; AD 32 inhibited the binding of [3H]PDBu to PKC. Therefore, AD 32 competes with the tumor promoter for the PKC binding site and prevents the latter from both interacting with the phospholipid and binding to PKC. These effects of AD 32 were reproduced in situ; incubation of human leukemia ML-1 cells with TPA showed an increased phosphorylation of cellular proteins, and the TPA-induced protein phosphorylation was inhibited by the addition of AD 32 to the cultured cells.

Binding, Competitive↗
PubMed1986

Synaptic remodelling in arcuate nucleus after injection of estradiol valerate in adult female rats.

Adult female rats were injected with a single dose (20 mg/kg) of estradiol valerate (EV). The number of synapses was evaluated in thin sections of arcuate nucleus fixed 3, 8, 16 and 32 weeks after EV treatment and compared with the values obtained in the arcuate nucleus of uninjected proestrus control rats. By 8 weeks after EV treatment a significant (P less than 0.001) decrease was found in the number of axo-somatic and axo-dendritic synapses on dendritic shafts, but not in the number of axo-dendritic synapses on dendritic spines. However, by 32 weeks postinjection, the number of axo-somatic and axo-dendritic synapses had returned to control values. This transient decrease in the number of synapses was preceded by a massive appearance of neuronal degenerative images by 3 weeks after EV injection. These results are interpreted as reflecting a process of circuitry remodelling in the arcuate nucleus after a neuronal lesion induced by estrogen.

Animals↗
PubMed1990

Glial peroxidase activity in the hypothalamic arcuate nucleus: effects of estradiol valerate-induced persistent estrus.

To test the hypothesis that stimulation of glial peroxidase activity by estrogens may play a role in the pathogenesis of the previously reported degenerative changes in the hypothalamic arcuate nucleus that occur in female rats treated with a long-acting estrogen preparation, the cellular localization and number of peroxidase-positive granules in the hypothalamus were determined in adult female rats treated with a single intramuscular injection of 2 mg of estradiol valerate. The persistent estrus state, manifested as persistent vaginal cornification and polycystic ovaries, was induced in 80% of the animals. In comparison with normally cycling controls, the arcuate nuclei of persistent estrus rats exhibited a 3- and 2.8-fold increase in numbers of diaminobenzidine-positive granules and granule clusters, respectively (P less than 0.01 for both comparisons). These peroxidase-positive granules were identified in astrocytes by double-label immunohistochemistry utilizing antiserum to glial fibrillary acidic protein. Diaminobenzidine staining occurred over a pH range of 4-10.5 and was resistant to the catalase inhibitor, aminotriazole, and to tissue pre-heating, indicating that the histochemical reaction was not due to tissue enzyme activity. Rather, these findings indicate that a non-enzymatic, pseudoperoxidation reaction has been induced in these cells by estrogen administration. Possible mediators of this reaction are metallo-porphyrins known to be present in rodent hypothalamus. The mechanisms by which astrocyte peroxidase activity may play a role in estrogen-related neural damage are discussed.

Animals↗
PubMed1985

Indian Council of Medical Research. Task Force on Hormonal Contraception: Phase II randomized clinical trial with norethisterone oenanthate 50 mg alone and in combination with 5 mg or 2.5 mg of either estradiol valerate or cypionate as a monthly injectable contraceptive.

A Phase II multicentric study was carried out to compare the different contraceptive treatment schedules of the monthly injectable consisting of norethisterone oenanthate (NET OEN) 50 mg either given alone or in combination with estrogen esters, 2.5 or 5 mg of estradiol valerate (E2 Val.) or estradiol cypionate (E2 Cyp.). A total of 364 women were observed for 1686 months of use. Analysis of the bleeding pattern data indicated that NET OEN 50 mg when given alone gave rise to delayed cycles and/or amenorrhoea. However, the addition of estrogen esters in a dose of either 2.5 or 5 mg provided significantly better bleeding patterns. Of the different treatment schedules investigated, the combination of NET OEN 50 mg with E2 Val. 5 mg provided more consistent and better cycle control. These findings however need further validation on a larger study sample.

Adult↗
PubMed1990

A multicentre phase III comparative study of two hormonal contraceptive preparations NET-OEN (50 mg) + E2 valerate (5 mg) given every month and NET-OEN (200 mg) given every 2 months as intramuscular injection--a report of 12-month study. Indian Council of Medical Research Task Force on Hormonal Contraception.

A phase III randomized clinical trial was undertaken to compare the efficacy, side effects and acceptability of a combined monthly injectable preparation containing NET-oenanthate (NET-OEN) (50 mg) plus oestradiol valerate (E2 Val.) (5 mg) with NET-OEN only (200 mg) given every two months. A total of 849 subjects were observed for 7817 woman-months of contraceptive use. Net discontinuation rates due to involuntary pregnancy at 12 months were 0.2 and 1.1 per 100 users for one monthly and two monthly injectable preparations, respectively. Although the monthly preparation was found to be efficacious and the subjects using the monthly preparation had a better bleeding pattern, the net discontinuation rate at 12 months due to menstrual disturbances did not show any significant difference between the two preparations. With proper counselling and motivational strategies, it is likely that acceptability of monthly injectables can be further enhanced.

Adolescent↗
PubMed1991

A multicentred, two-year, phase III clinical trial of norethisterone enanthate 50 mg plus estradiol valerate 5 mg as a monthly injectable contraceptive.

Norethisterone enanthate (NET-EN) 50 mg combined with estradiol valerate (EV) 5 mg was studied as a once-a-month injectable contraceptive with regard to effectiveness, cycle control, adverse events and acceptability. In eight Family Planning Centres from 5 Latin American countries, 652 fertile women were followed-up for a period of 24 months, providing a total of 10,689 woman-months of experience. Only 1 pregnancy occurred, in the first treated month a few days before the second injection (failure rate 0.11 per 100 woman-years). Under treatment, the first cycle was drastically shortened in most cases, but thereafter cycles tended to recover to pre-treatment patterns. There was a significant decrease of hypermenorrhea and dysmenorrheic cycles. Intracyclic bleeding and spotting appeared in 1.2% and 2.4%, respectively, and amenorrhea in 2.5% of cycles. Incidence of other adverse events was very low with the exception of weight gain of 2 Kg (28%). Continuation rate at 12 months was 64.7%. The cumulative discontinuation rate due to bleeding problems was 7.4% and 10.7% due to adverse events at 24 months.

Adolescent↗
PubMed1994

Multicentred, phase III clinical trial of norethisterone enanthate 50 mg plus estradiol valerate 5 mg as a monthly injectable contraceptive; final three-year report.

Norethisterone enanthate (NET-EN) 50 mg combined with estradiol valerate (EV) 5 mg was studied as a once-a-month injectable contraceptive with regard to effectiveness, cycle control, adverse events and acceptability. In eight Family Planning Centres from five Latin American countries, 931 fertile women were followed-up for a period of 36 months, providing a total of 15,787 woman-months of experience. Only one pregnancy occurred: in the first treated month a few days before the second injection (failure rate 0.08 per 100 woman-years). Under treatment, the first cycle was drastically shortened in most cases, but thereafter cycles tended to recover to pre-treatment patterns. There was a significant decrease of hypermenorrhoea and dysmenorrheic cycles. Intracyclic bleeding and spotting appeared in 1.8% and 2.2%, respectively, and amenorrhea in 2.8% of cycles. The incidence of other adverse events was very low with the exception of weight gain of more than 2 kg (36.8%). The continuation rate at 12 months was 64.7%, at 24 months 31.0% and at 36 months 20.4%. The cumulative discontinuation rate due to bleeding problems was 6.1% and 7.2% due to adverse events at 36 months. The treatment was shown to be a highly effective contraceptive method that offers fairly good cycle control, good tolerance and a continuation rate that makes it suitable for use in family planning programmes in the Latin American area.

Amenorrhea↗
PubMed1992

Effects of estradiol valerate on the uterus of the musk shrew (Suncus murinus L.).

The effects of exogenous estradiol valerate on some uterine characteristics of the musk shrew were investigated. Treatment with the steroid for either 1 day or 7 days did not noticeably alter luminal epithelial cell height, endometrial gland epithelial cell height or diameter, or number of endometrial glands. The reciprocal values of cell density of circular muscle and deep endometrial layers and endometrium-to-myometrium ratio of the uterus increased significantly in response to 7 days of steroid administration. After 1 day of steroid treatment the numbers of mast cells in different layers of the uterus (i.e., meso-, myo-, and endometrium) were unchanged, but after 7 days there were significant increases in the number of mast cells in meso- and myometria. The number of eosinophils in all three layers of the uterus increased significantly in response to the treatment of estradiol for 1 day or for 7 days. The increase was greater in the 7-day group. Neither uterine DNA nor RNA contents changed following administration of the steroid for either group, although protein content was elevated significantly in the 7-day group. Estradiol administration thus evokes small but subtle changes in the uterus of the musk shrew.

Animals↗
PubMed1981

Gonadotropic and ovarian hormone response in dairy cows treated with norgestomet and estradiol valerate.

Injection of estradiol valerate in conjunction with receiving a norgestomet ear implant (Syncro-Mate-B) reduced plasma progesterone (P<.001) and FSH (P<.02) and increased estradiol (P<.01) in postpartum cows during the treatment period. Occurrence of LH and FSH peaks (P<.05) varied between 12 and 48 hr following removal of SMB implants and estrous behavior was minimal. FSH was strongly correlated to LH and was inversely related to progesterone in untreated cows and to estradiol in treated cattle. Syncro-Mate-B suppressed luteal activity and peak gonadotropin release during treatment and elicited variable endocrine and behavioral response following treatment.

Journal Article↗
PubMed1984

Estrus and ovulation in beef cows following use of progesterone-releasing devices, progesterone and estradiol valerate.

Two hundred nonsuckling beef cows were treated with either 1) a progesterone-releasing intravaginal device (PRID) for 12 days; 2) PRID plus an IM injection of 200 mg progesterone (PRID-P); 3) PRID plus 5-mg IM injection of estradiol valerate (PRID-EV); or 4) PRID-EV-P. Cows were started on treatment on one of the first eight days of the estrous cycle. The number of cows which had P levels above 1 ng/ml one day after PRID removal was 12 to 50% lower in PRID-EV and PRID-EV-P groups than in PRID and PRID-P groups (P < 0.05). The proportion of cows showing estrus by 96 hours after PRID removal was 38, 36, 77, and 88% (P < 0.05) for the PRID, PRID-P, PRID-EV and PRID-EV-P groups, respectively. Thirty-one percent fewer cows treated with PRID on days 5 through 8 of the estrous cycle showed estrus by four days after PRID removal than those treated on days 1 through 4. In addition, 18 to 22% more cows had P levels above 1 ng/ml among cows treated with PRID or PRID-P on days 5 through 8 than among cows treated similarly on days 1 through 4. It was concluded that effective synchronization of estrus is achieved only when estrogen is used in conjunction with PRID in cows treated for twelve days during the first eight days of an estrous cycle.

Journal Article↗
PubMed1995

Ultrasonography and endocrinology of ovarian dysfunctions induced in heifers with estradiol valerate.

This study monitored the long-term follicular dynamics and changes in ovarian steroid hormones associated with an experimental model of cystic ovarian degeneration (COD) in the heifer. In the treated group (n = 7), Holstein heifers received a single injection of 500 microg of cloprostenol (prostaglandin F2a, PG) and 5 mg of estradiol valerate (EV) on either Day 17, 18 or 19 of the estrous cycle. The control group (n = 7) received only PG. Transrectal ultrasound was performed daily, beginning 8 to 10 d before injection and continuing until a return to normal cyclicity (40 to 74 d). Blood samples were taken twice daily over the same period. The EV disrupted the normal follicular development as well as the plasma progesterone and estradiol profiles of 6/7 heifers in the treated group. Two different types of responses were observed. The Type-I response (n = 2) was characterized by a premature ovulation followed by a corpus luteum (CL) which persisted for over 30 d. The Type-II response (n = 4) was characterized by anovulation followed by the emergence of a large ovarian structure which could further be subtyped. In Type- IIA (n = 2), this follicle ovulated at an exaggerated size of 19 or 24 mm (mean diameter of controls: 13.4 +/- 2.7 mm). The subsequent cavernous CL was very large at 35 and 37 mm (mean diameter of CL in controls: 23.8 +/- 2.0 mm). In Type- IIB (n = 1), the follicle present at the time of injection continued to grow and became a luteinized cyst. In Type-IIC (n = 1), several waves of follicular cysts developed and persisted for 52 d. This study suggests that EV induces a range of ovarian dysfunctions including different forms of COD. The individual differences in the stage of folliculogenesis at the time of injection of EV may be responsible for the different types of responses.

Journal Article↗
PubMed1995

Estrus after treatment with Syncro-Mate B* in ovariectomized heifers is dependent on the injected estradiol valerate.

A series of experiments was conducted to determine why ovariectomized heifers exhibit estrus after they are treated with the estrus synchronization product, Syncro-Mate B(*) (SMB). In Experiment 1, 23 of 40 (58%) ovariectomized heifers exhibited estrus after treatment with SMB. The mean concentration of estradiol-17beta (E(2)) in serum was lower (P < 0.001) before treatment than after implant removal in ovariectomized heifers treated with SMB. Six of 10 heifers from which serum was collected to determine concentrations of LH exhibited estrus and 5 of 6 had a surge of LH in serum after implant removal. In Experiment 2, when no estradiol valerate (EV) was given or when the norgestomet implant period was extended from 9 to 18 d, no heifer exhibited estrus after implant removal. The mean concentration of E(2) for 3 d after implant removal was lower (P < 0.001) in ovariectomized heifers with implants for 18 d versus those with implants for 9 d and was also lower (P < 0.001) in ovariectomized heifers treated only with norgestomet compared with those receiving the standard SMB treatment. When estradiol-17beta was substituted for EV in the SMB treatment, serum E(2) was lower (P < 0.001) after implant removal than in heifers receiving the standard SMB treatment. Experiment 3 demonstrated that combining a norgestomet implant or implant plus a 3-mg injection of norgestomet with EV did not alter concentrations of E(2) in serum on the days when synchronized estrus would be expected following SMB treatment. The results indicate that the SMB-induced estrus in ovariectomized heifers is dependent upon EV in the SMB treatment. Apparently, EV elevates the concentration of E(2) in serum, and the E(2) remains sufficiently high to induce estrus after implant removal.

Journal Article↗
PubMed1984

Apolipoprotein A1 levels in oophorectomized women treated with Org OD 14, oestradiol valerate and a placebo.

Org OD 14 is a synthetic steroid which in animal bioassays displays oestrogenic as well as very weak androgenic-anabolic properties. Earlier studies have shown that it alleviates oestrogen-deficiency symptoms and retards osteoporosis. OD 14 can be administered continuously with little effect on the endometrium. The aim of this study was to evaluate the effect of OD 14 on apolipoprotein A1 (Apo-A1), the major protein constituent of the high-density lipoprotein (HDL) fraction, as compared with that of oestradiol valerate (E2V) and a placebo. Twenty-two women, who had been oophorectomized when undergoing surgical treatment for stage IB or IIA cervical carcinoma, were given OD 14 2.5 mg/day, a placebo, and E2V 2 mg/day for a period of 6 wk in each case using a double-blind, cross-over method. Serum Apo-A1 was determined by electro-immunoassay after each treatment period. There was a marked decrease in Apo-A1 after OD 14 as compared with the levels seen after the placebo and E2V. This decrease is interpreted as evidence of a strong androgenic influence by OD 14. In epidemiological studies low levels of Apo-A1 have been associated with a higher incidence of atherosclerosis and cardiovascular disease. Long-term treatment with OD 14 might therefore be hazardous in this respect.

Adult↗
PubMed1987

Dose and duration effects of oestradiol valerate on serum apolipoproteins A1 and B.

The serum levels of apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) were assessed by electroimmunoassay in 19 bilaterally oophorectomised women before and after treatment with 2 and 4 mg oestradiol valerate (E2V) daily. The first part of the study was conducted in accordance with an open cross-over design. The levels of ApoA1 were found to have increased after the 6-week treatment periods using each of those dosages, the increase being most pronounced after treatment with 4 mg E2V. ApoB concentrations decreased at both dosage levels. The serum levels of total (TC) and free cholesterol (FC) and phospholipids (PL) in the high-density lipoprotein (HDL) fraction correlated positively with the serum levels of ApoA1 before treatment. The correlations between serum ApoA1 and HDL-PL levels persisted after both dosage regimens. Before and after treatment with 2 mg E2V, serum ApoB levels correlated positively with the levels of all lipid components in the low-density lipoprotein (LDL) fraction. After 4 mg E2V, serum ApoB levels correlated positively with LDL-PL and LDL-TC levels. On conclusion of the cross-over, in order to assess the effects of the duration of therapy, the women were followed up for a further period of 3 mth, during which ten were given 2 mg and the other nine 4 mg of E2V daily. The increased levels of ApoA1 and the decreased levels of ApoB seen after the cross-over study were not found to have altered after this treatment-duration evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

A comparison of the effects of ethinyl estradiol and estradiol valerate on serum and lipoprotein lipids.

Serum lipids and lipoproteins were assessed after treatment with 2 mg of oestradiol valerate (E2V) and 10 micrograms of ethinyl oestreadiol (EE) in a group of 24 oophorectomised women in a study with an open cross-over design. E2V in this oral dose was quite inert in its effect on lipoprotein lipids. Ten micrograms of EE is a dose which in most women is sufficient to alleviate post-menopausal vasomotor symptoms. However, this low dose of EE increased serum triglycerides as a result of increased levels in the ultracentrifugally isolated lipoprotein fractions. Increased levels of serum and lipoprotein triglycerides are considered cardiovascular risk factors in women.

Adult↗
PubMed1988

Treatment of climacteric complaints with Org OD 14: a comparative study with oestradiol valerate and placebo.

Org OD 14 (7 alpha,17 alpha-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) is a steroid possessing mixed hormonal activity, which in earlier studies has been shown to alleviate climacteric complaints and to prevent post-menopausal osteoporosis without affecting the endometrium. The effects of Org OD 14 on climacteric complaints were compared with those of oestradiol valerate (E2V) and placebo in a randomized, double-blind, cross-over study in 20 women who had been oophorectomized and hysterectomized 3-6 yr earlier as part of their treatment for cervical cancer. Each patient was treated orally for a total period of 18 wk, comprising 6 wk on each preparation. Capsules of identical appearance were given; these contained either 2.5 mg Org OD 14, 2 mg E2V or placebo. The patients' scores for symptoms and mood items on standardized rating scales were recorded at the end of each 6-wk treatment period (i.e. on days 43, 85 and 127). There were no differences between the effects of Org OD 14 and E2V on symptoms and mood items, while both compounds were more effective than placebo. Our findings confirmed that Org OD 14 is effective in ameliorating oestrogen deficiency symptoms in climacteric women.

Adult↗
PubMed1990

Pharmacokinetics and biotransformation of orally administered oestrone sulphate and oestradiol valerate in post-menopausal women.

The pharmacokinetic properties and biotransformation of two orally active oestrogens, piperazine oestrone sulphate (PE1S, 2.5 mg/day) and oestradiol valerate (E2V, 2.0 mg/day), given alone or in combination with levonorgestrel (LNG, 250 micrograms/day) were compared in 8 post-menopausal women, using a randomized cross-over design. The end points measured in peripheral plasma included oestrone (E1), oestradiol (E2), oestriol (E3), oestrone sulphate (E1S), oestradiol sulphate (E2S) and oestriol sulphate (E3S). In addition, LNG and sex-hormone-binding globulin SHBG concentrations were also assessed. The plasma levels of E3 were invariably below the detection limit (220 pmol/l). The levels of all the other oestrogens analyzed were consistently higher and the area under the curve significantly greater (except in the case of E3S) following PE1S administration than those recorded after E2V ingestion. The terminal half-lives of the circulating oestrogens measured after PE1S administration did not differ from those found after E2V administration. After 21 days of PE1S administration (in combination with LNG for the last 10 days), the maximum levels of all the oestrogens (except those of E2) were significantly higher than those seen after the first dose. No such difference was observed after E2V administration. There was no difference between the effects of the two treatment regimens with regard to the E1/E2 ratios, but the E1/E1S ratios were significantly lower after PE1S treatment than after E2V administration. It is concluded that, compared with an equivalent dose of PE1S, daily repeated oral administration of E2V yields consistently lower peripheral plasma levels of E2 and its principal metabolites. However, in contrast to PE1S therapy, prolonged administration of E2V does not result in an accumulation of the circulating oestrogens measured.

Administration, Oral↗