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PubMed1987

Cytosol estradiol receptor content in the adult rat brain after neonatal treatment with estradiol benzoate or testosterone propionate.

The effects of neonatal treatment with estrogen or androgen on the development of cytosol estradiol (E2) receptors were examined in the rat pituitary, hypothalamus and amygdala. The treatment with estradiol benzoate (EB, 100 micrograms) significantly reduced the E2 receptor content in all of these regions in both sexes. But the treatment with testosterone propionate (TP, 1 mg) to the female rats significantly decreased the E2 receptor content in the pituitary and hypothalamus but not in the amygdala. The TP treatment to the male rats decreased the E2 receptor content in the hypothalamus and amygdala but not in the pituitary. The decreased cytosol E2 receptors in the hypothalamus and amygdala seem to be implicated in preventing the normal sexual development.

Amygdala↗
PubMed1981

17 Alpha-ethinyl estradiol is more potent than estradiol in receptor interactions with isolated hepatic parenchymal cells.

Estradiol (E2) and 17 alpha-ethinyl estradiol (EE2) were compared for their abilities to promote nuclear translocation of the hepatic estrogen receptor. High levels of nonradioactive E2 and EE2 were incubated in vitro with isolated rat liver parenchymal cells. Cytosol and nuclear receptors were then partially purified and measured by exchange with [3H]E2. E2 was required in an approximately 100-fold higher concentration than EE2 for promotion of receptor translocation (for example, 10(-5) M E2 was equivalent to 10(-7) M EE2). When the metabolisms of the estrogens by parenchymal cells were compared, it was found that [3H]E2 was metabolized much more extensively than [3H]EE2 after a short time interval. Inhibitors of estrogen metabolism were used to test the hypothesis that the high dose requirement for receptor translocation may be due to metabolism. In isolated liver cells, SKF 525A (beta-diethylaminoethyl-2,2-diphenylpentanoate; an inhibitor of hepatic mixed function oxidase) could increase levels of unmetabolized EE2, cytosol receptor deletion, and nuclear receptor accumulation. SKF 525A alone was not sufficient to increase levels of unmetabolized E2 or receptor translocation in the presence of this estrogen. When testosterone (a transient inhibitor of the 17-oxidoreductase active on E2) was included in cellular incubations (using female liver cells) with E2 and SKF 525A, levels of unmetabolized E2 were substantially increased in conjunction with increased depletion of cytosol receptors and increased levels of nuclear receptors. These data suggest that hepatic metabolism may limit the availability of estrogens for binding to receptors. The present study suggests that E2 is more extensively metabolized than EE2 to metabolites which are less capable of promotion of receptor translocation.

Animals↗
PubMed2003

17beta-estradiol-induced activation of ERK1/2 through endogenous androgen receptor-estradiol receptor alpha-Src complex in human prostate cells.

We examined the effect of estrogens on mitogen-activated protein kinase (MAPK) in EPN cells, a line of epithelial cells derived from human normal prostate. 17beta-estradiol (E2) caused a rapid and transient activation of MAPK (ERK1/2) within 5 min. This effect was counteracted by the anti-estrogen ICI 182-780 and by MEK inhibitor PD098059. The activation of ERK1/2 through 17beta-estradiol triggered simultaneous association of endogenous androgen receptor, estrogen receptor alpha and Src. In addition, E2 stimulated the proliferation of EPN cells, suggesting that the formation of the ternary complex and the consequent activation of ERKs are implicated in the mechanism regulating proliferation of epithelial prostate cells.

Blotting, Western↗
PubMed1989

A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters.

Ethinyl estradiol (EE) is still used to some extent as hormonal replacement therapy (HRT) in the climacteric period. As regards oral contraception, it is well known that the induced increase in cardiovascular disease is related to the estrogen component (invariably EE) in a dose-related fashion. Considerably lower doses of EE are needed in HRT compared to oral contraception. To delineate and compare effects of EE and estradiol valerate (E2V) in doses needed in HRT on haemostasis parameters, 24 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (10 micrograms EE and 2 mg E2V daily) are the lowest which eliminate climacteric symptoms in a majority of women. Unlike E2V, EE caused increased levels of factor VII:Ag, factor VIII:C and beta-thromboglobulin, which may be changes towards hypercoagulability. Both estrogens decreased the AT III activity. Long-term administration (6 + 12 w) of the estrogens induced further changes in haemostatic parameters. 10 micrograms EE increased factor VII:Ag in contrast to 2 mg E2V. Furthermore both estrogens increased factor VIII:C and factor II-VII-X. A decrease in platelet count was induced by both EE and E2V. Oral contraception and adjuvant estrogen therapy in men with prostatic carcinoma are known to imply an increased cardiovascular risk. It is noteworthy that the pattern of changes in haemostatic parameters induced by as little as 10 micrograms of EE is the same as seen after the administration of combined oral contraceptives or the substantially higher doses of EE given as adjuvant therapy to men with prostatic carcinoma.

Adult↗
PubMed1990

Dissolution testing of norethindrone:ethinyl estradiol, norethindrone:mestranol, and norethindrone acetate:ethinyl estradiol combination tablets.

Dissolution of oral contraceptive combination products from six manufacturing firms was studied utilizing the rotating basket method at 100 rpm in 600 mL of 0.1 M HCl and 0.02% sodium lauryl sulfate (SLS). Most of the combination products of norethindrone (NE):ethinyl estradiol (EE) dissolved satisfactorily in water using the paddle method which was first proposed by U.S.P., whereas three of 18 tested products showed better dissolution in acidic aqueous medium containing SLS. Acidic medium with surfactant was also found to be suitable for combination products of norethindrone (NE):mestranol (ME) and norethindrone acetate (NEAc):ethinyl estradiol (EE). A modified U.S.P. assay procedure, a reversed-phase high-performance liquid chromatographic (HPLC) method with a mobile phase of acetonitrile and phosphate buffer, was used to analyze NE and EE concurrently. The NEAc and ME were analyzed separately in these combination products. The NEAc was found to hydrolyze to some extent (approximately 20% in 8 h) in acidic dissolution medium at room temperature, but less so at 4 degrees C. The NE was identified as the sole degradation product of NEAc hydrolysis and was also measured to account for the total amount of NEAc dissolved. A simple dissoluting testing method which utilizes a single dissolution medium was applicable for all oral contraceptive combination tablets surveyed.

1-Propanol↗
PubMed1979

Studies on the mechanism of estradiol uptake by rat uterine cells and on estradiol binding to uterine plasma membranes.

A method for the preparation of viable uterine cell suspensions is described. Using this system the kinetics of estradiol uptake were studied in order to asses whether the steroid enters uterine cells by passive diffusion (1) or protein mediated diffusion (2). The data presented show that a) the rates of estradiol entry are nonsaturable; b) temperature dependence of uptake kinetics gives a linear Arrhenius plot; c) E2-6-CMO-BSA does not inhibit 3H-E2 uptake; d) uterine plasma membranes do not contain specific estrogen binding sites. Thus, estrogen uptake occures by passive diffusion.

Animals↗
PubMed1989

Effect of progestins, estradiol, and coenzymes NAD and NADPH on the interconversion of estradiol and estrone in rabbit uterus in vitro.

The biotransformation of estradiol (E2) and estrone (E1) in the uterus of rabbits treated with norgestrel (NG), norethindrone (NET), norethindrone acetate (NETA), progesterone (P4), and E2 either by subcutaneous injection in oil or by intrauterine steroid-releasing silastic implants was carried out under an in vitro short-term incubation system. The studies have shown that E2 stimulates 17 beta-hydroxysteroid dehydrogenase (17 beta-OHSD) much more than P4 as compared to untreated controls. The kinetic studies on E2 metabolism in the presence of added coenzyme NAD showed an initial rapid estrone formation and a gradual reconversion of E1 to E2. The addition of NADPH, ATP, and glucose-6-phosphate facilitates the reconversion of E1 to E2. The interconversion of E2 and estrone in the presence of coenzymes was five- to ten-fold higher in the endometrium than in the myometrium per milligram protein. Both E2 and progestins stimulate the uterine 17 beta-OHSD activity in rabbit uterus. This study further suggested that the hormone-induced metabolism of estradiol and estrone in the rabbit uterus is essentially modulated by the availability of coenzymes.

17-Hydroxysteroid Dehydrogenases↗
PubMed1977

A study of prostaglandin F2alpha as the luteolysin in swine: III effects of estradiol valerate on prostaglandin F, progestins, estrone and estradiol concentrations in the utero-ovarian vein of nonpregnant gilts.

Polyvinyl catheters were placed into the right and left utero-ovarian veins and saphenous vein and artery of three control (C) and four estradiol valerate (EV) treated gilts on Day 9 after onset of estrus. The EV treated gilts received 5mg EV/day on Days 11 through 15 after onset of estrus. On Days 12 through 17 utero-ovarian vein blood samples were collected at 15 min intervals from 0700 to 1000 hr and 1900 to 2200 hr and single samples were taken at 1100 and 2300 hr. Peripheral blood samples (saphenous vein or artery) were taken at 0700, 1100, 1900 and 2300 hr from Day 12 until the control gilts returned to estrus or until Day 25 for EV treated gilts and used to measure plasma steroid hormone concentrations. Utero-ovarian vein prostaglandin F (gf) concentrations (ng/ml, n-1,177) were measured by RIA. Status (control vs EV treated gilts) by day interactions were detected (P=.10). Curvilinear day trends were detected for plasma PGF concentrations in control (P less than .01) but not EV treated gilts. PGF concentrations (X +/- S.D.) for control and EV treated gilts were 1.20 +/- 2.08 and .26 +/- .84 ng/ml, respectively. PGF peaks (concentrations greater than X + 2 S.D.) occurred with greater frequency in control gilts (X2 =4.87; P less than .05). The interestrus interval (X +/- S.E.) for control and treated gilts was 19.0 +/- .6 and 146.5 +/- 74.8 days, respectively. Data indicate tht t estradiol valerate may exert its luteotrophic effect by preventing PGF release from the uterus.

Animals↗
PubMed1976

Effect of subcutaneous vs intraperitoneal administration of an anti-estrogen, CI-628, estradiol-and estradiol benzoate-stimulated lordosis in the ovariectomized rat.

The anti-estrogen CI-628 (3 mg) inhibited estradiol (E, 150 mug, SC in oil)-stimulated lordosis in ovariectomized rats, when the anti-estrogen was given intraperitoneally (IP) at the time of E injection (Hr 0). No lordosis inhibition occurred after similar treatment, if the CI-628 was given subcutaneously. For estradiol benzoate (EB, 2 mug, SC in oil)-stimulated lordosis, CI-628 (Hr 0) had a substantial inhibitory effect whether it was given IP or SC, the greater percentage inhibition occurring after SC CI-628 (Experiment 1). All animals received sequential injections of estrogen and progesterone (500 = s,g, SC in oil) and were then tested to 10 mounts by an intact male. These results suggested that, after E injection, neural tissues mediating lordosis have a shorter period of sensitivity to the behavioral effects of CI-628 than after EB injection. Thus, inhibition of E-stimulated lordosis apparently required the more rapid onset of intracellular estrogen retention inhibition resulting from CI-628 given IP rather than SC. This was not the case for EB-stimulated lordosis, where a longer period of sensitivity to CI-628 seeemed likely. This hypothesis was supported by the data of Experiment 2, in which CI-628 (3 mg, IP) was first given 3 hr after E or EB treatment. In this paradigm, CI-628 no longer inhibited E-stimulated lordosis. In contrast, the anti-estrogen's effect on EB-stimulated lordosis was at least equal to the inhibition occurring after CI-628 (IP) given at Hr 0.

Animals↗
PubMed1991

Comparison of cytochrome P-450 species which catalyze the hydroxylations of the aromatic ring of estradiol and estradiol 17-sulfate.

For identification of microsomal cytochrome P-450 (P-450) enzymes which catalyze 2- or 4-hydroxylations of estrogens in the rat liver, estradiol (E2) and estradiol 17-sulfate (E2-17-S) were selected as the substrates and incubated with various kinds of purified P-450 enzymes: PB-1, PB-2, PB-4 and PB-5 obtained from phenobarbital-treated male rats (Sprague-Dawley); MC-1 and MC-5 from 3-methylcholanthrene-treated male rats; and UT-1, UT-2, UT-4 and UT-5 from untreated animals. The reactions were carried out under the P-450-reconstructed system, and the resulting products were determined by HPLC using electrochemical detection. All the enzymes tested were shown to have varying degrees of catalytic activities for 2-hydroxylation of the two substrates; UT-1 and UT-2 had the highest activity. Of the induced P-450 enzymes, PB-2 and MC-1 showed fairly high catalytic activity for 4-hydroxylation of E2. The P-450 enzymes obtained from the untreated male rats, especially UT-4, showed the highest catalytic activity for 4-hydroxylation of the two substrates. From these results and also from kinetic experiments, the P-450 enzymes which catalyze 2- and 4-hydroxylations of estrogen were considered to be different species. A part of E2 was converted to such metabolites as estrone and those having a hydroxyl group at positions 6 beta, 15 alpha or 16 alpha, each production of which was estimated to be catalyzed by single or multiple P-450s.

Animals↗
PubMed2005

Plasma concentrations of estradiol and testosterone, gonadal aromatase activity and ultrastructure of the testis in Xenopus laevis exposed to estradiol or atrazine.

The ultrastructure of testicular cells of adult male African clawed frogs (Xenopus laevis) exposed to either estradiol (0.1 microg/L) or 2-chloro-4-ethylamino-6-isopropyl-amino-s-triazine (atrazine; 10 or 100 microg/L) was examined by electron microscopy and compared to plasma concentrations of the steroid hormones, testosterone (T) and estradiol (E2), testicular aromatase activity and gonad growth expressed as the gonado-somatic index (GSI). Exposure to E2 caused significant changes both at the sub-cellular and biochemical levels. Exposure to E2 resulted in significantly fewer sperm cells, inhibition of meiotic division of germ cells, more lipid droplets that are storage compartments for the sex steroid hormone precursor cholesterol, and lesser plasma T concentrations. Although not statistically significant, frogs exposed to E2 had slightly smaller GSI values. These results may be indicative of an inhibition of gonad growth and disrupted germ cell development by E2. Concentrations of E2 in plasma were greater in frogs exposed to E2 in water. Exposure to neither concentration of atrazine caused effects on germ cell development, testicular aromatase activity or plasma hormone concentrations. These results suggest that atrazine does not affect testicular function. In contrast, exposure of male X. laevis to E2 led to sub-cellular events that are indicative of disruption of testicular development, and demasculinization processes (decrease of androgen hormone titers). These results indicate that atrazine does not cause responses that are similar to those caused by exposure to E2.

Analysis of Variance↗
PubMed2005

Serum Nestorone and ethinyl estradiol levels, and ovulation inhibition in women using three different dosage combinations of a Nestorone progestogen-ethinyl estradiol contraceptive vaginal ring on a bleeding-signaled regimen.

OBJECTIVES: This trial tested the hypothesis that menstrually signaled use of contraceptive vaginal rings ("rings") releasing low-dose combinations of Nestorone (NES) and ethinyl estradiol (EE) would reliably suppress luteal activity and ovulation, and prevent unintended pregnancy, while controlling the incidence of menstrual bleeding episodes and bleeding days. METHODS: Nestorone/ethinyl estradiol rings releasing 50/10, 50/20 and 150/15 mug/day were studied through 6 months. A ring was to be used continuously, until its removal was signaled by menstrual bleeding. Reinsertion was required 96 h after removal. Serum for NES, EE and progesterone were collected and assayed, and vaginal ultrasound scans were performed in three 5-week periods to examine luteal activity, follicular growth, ovulation and their correlates. In 10 subjects using the 150/15 ring, six samples were drawn in the 24-h period after ring removal to examine serum levels of NES and EE. RESULTS: One hundred sixty subjects at three doses provided blood samples. Median serum concentrations of NES and EE demonstrated dose ratios slightly below the nominal dose ratios expected. Serum NES concentrations declined 19-22% from weeks 3 to 25. Changes in EE levels depended on dose. Nestorone levels fell 81% by 24 h after ring removal and EE levels fell by 50%. Luteal activity was completely suppressed in 94-95% of cycles and in 90% of subjects. Three pregnancies occurred in subjects participating in this serum sampling study. CONCLUSION: Satisfactory serum levels of NES and EE, and a high level of ovulation suppression were achieved. Irregular ring use, however, permitted pregnancies to occur.

Contraceptive Agents, Female↗
PubMed2006

A prospective study on the effects on hemostasis of two oral contraceptives containing drospirenone in combination with either 30 or 20 microg ethinyl estradiol and a reference containing desogestrel and 30 microg ethinyl estradiol.

PURPOSE: In this open-label, randomized study, we assessed the effects on hemostasis of two combined oral contraceptives containing drospirenone (DRSP) as progestogen component. METHODS: Three milligrams of DRSP, a progestogen with antimineralocorticoid activity, was combined with either 30 or 20 microg ethinyl estradiol (EE) (DRSP/30EE; DRSP/20EE) and compared with a preparation containing 150 microg desogestrel (DSG) and 30 microg ethinyl estradiol (DSG/30EE). A total of 75 healthy female volunteers aged 18-35 years were enrolled. The hemostasis variables were measured in the medication-free precycle (baseline); in the first, third and sixth treatment cycle; and in the follow-up phase. The target variables for comparison were the relative changes from baseline to Cycle 6. RESULTS: Data of 25 volunteers in each group were valid for the per-protocol evaluation. Most changes in hemostasis variables were similar in the three treatment groups. All procoagulatory variables and the anticoagulatory variable protein C antigen increased slightly, while protein S antigen and activity decreased. For fibrinogen and protein S activity, the changes were statistically significant: less pronounced with DRSP/20EE compared to DSG/30EE at Cycle 6. There were no statistically significant differences in the changes of antifibrinolytic variables, the global clotting tests and D-dimer. All pairwise comparisons of DRSP/30EE vs. DSG/30EE yielded nonsignificant results; however, there was a trend of a lower impact of DRSP/20EE on nearly all hemostatic parameters compared to the 30EE products. All three study treatments were safe and well tolerated by the volunteers and provided adequate contraceptive reliability. CONCLUSION: The changes in the hemostatic variables for DRSP/20EE were less pronounced compared to DSG/30EE and DRSP/30EE. The results were in accordance with previous reports on effects of similar OCs.

Adolescent↗
PubMed2004

Effects of neonatal administration of 17beta-estradiol, beta-estradiol 3-benzoate, or bisphenol A on mouse and rat spermatogenesis.

Bisphenol A (BPA) is a global environmental contaminant that has been implicated as a potential endocrine disruptor. In the present study, newborn rats and mice were injected subcutaneously with BPA to determine the potential developmental effects on the testis. Testes were examined by light and electron microscopy at 15 weeks of age. Other groups of newborn mice and rats were injected with 17beta-estradiol (E2) or beta-estradiol 3-benzoate (E2B) in a similar manner. BPA, E2, and E2B had similar effects on testes. When treated animals reached puberty and spermiogenesis began, the first sign of the effects was detected in the steps 2-3 spermatids: the acrosomal granule and nucleus were deformed. Henceforth, abnormalities in the acrosome and nucleus were observed in older spermatids and spermatozoa. Ectoplasmic specialization between the Sertoli cell and spermatids was also affected: some specializations were partially or totally deleted. When animals fully matured, the effects of the agents were not found in the testes, and the animals were found to be fertile. The results of the present study show that BPA acts as an estrogen, and causes changes which appear to revert in adults.

Animals↗
PubMed2000

Bleeding patterns of women using Lunelle monthly contraceptive injections (medroxyprogesterone acetate and estradiol cypionate injectable suspension) compared with those of women using Ortho-Novum 7/7/7 (norethindrone/ethinyl estradiol triphasic) or other oral contraceptives.

Persistent and/or unpredictable bleeding is a common reason for discontinuation of hormonal contraceptive methods. An open-label, nonrandomized, parallel, controlled study compared the efficacy, safety, and cycle control of the new, highly efficacious monthly injectable contraceptive containing 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate (E(2)C) (MPA/E(2)C) (Lunelle Monthly Contraceptive Injection) with that of the frequently used norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum 7/7/7). This report directly compares the bleeding patterns of women on MPA/E(2)C to those of women on NET/EE and untreated women. Overall, breakthrough bleeding occurred less frequently in women using MPA/E(2)C than in women using NET/EE (p < or =0.01). However, more women using MPA/E(2)C experienced amenorrhea/missed periods than those on NET/EE (p < or =0.01). In addition, the percentage of women experiencing breakthrough bleeding or amenorrhea while using other oral contraceptives is compared to that of women using MPA/E(2)C. A rapidly reversible method, MPA/E(2)C, combines the high contraceptive efficacy of surgical sterilization with the convenience of monthly administration. These data suggest that, for a large proportion of women, MPA/E(2)C offers predictability in bleeding patterns comparable to or greater than that experienced by ovulatory untreated women or those using combination oral contraceptives.

Adolescent↗
PubMed2000

Comparative effects of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic) on lipid profiles. Investigators from the Lunelle Study Group.

As part of a 60-week, open-label, nonrandomized, parallel, controlled study comparing a monthly contraceptive injection containing medroxyprogesterone acetate (MPA) 25 mg and estradiol cypionate (E(2)C) 5 mg (Lunelle Monthly Contraceptive Injection) and a norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum(R) 7/7/7), a longitudinal examination of lipid profiles was conducted. Lipid parameters were assessed at screening and at weeks 20, 40, and 60 (or the final visit) in 114 women using MPA/E(2)C and 93 using NET/EE (lipid analysis population). Extra blood samples were obtained at weeks 21, 22, and 23 in 61 MPA/E(2)C users and 51 NET/EE users (index-cycle analysis population) to investigate lipid changes during one cycle of use. In the index-cycle population, median changes from screening to week 60 showed a decrease in apolipoprotein (apo) A-I and apo A-II in both groups. MPA/E(2)C users had a decrease in total cholesterol (C), total triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), with maintenance of the total C/HDL-C ratio. NET/EE users showed an increase in total C and LDL-C, with no change in HDL-C or the total C/HDL-C ratio. Within the index cycle (weeks 20 to 23), median changes in lipid values in both MPA/E(2)C and NET/EE users were generally greatest during the first week after the injection or the start of the pill pack. The results of this first longitudinal examination of serum lipids in US women using MPA/E(2)C confirm earlier findings in women in other countries. However, a direct comparison of the effects of MPA/E(2)C and NET/EE on lipid profiles was not possible in this study because of its design and because of the baseline and pharmacokinetic/pharmacodynamic differences between the two contraceptive groups. The results of this analysis showed that, although overall lipid values decreased, including a significant decrease in HDL cholesterol, the maintenance of the total-C/HDL-C ratio suggests that the effect of MPA/E(2)C on lipid parameters may not negatively affect CVD risk over 1 year of use. However, these results warrant further investigation, given the nature of this trial.

Apolipoprotein A-I↗
PubMed1999

A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group.

OBJECTIVE: To determine whether a continuous estradiol-norethindrone acetate transdermal delivery system reduces incidence of endometrial hyperplasia in postmenopausal women more than transdermal estradiol (E2) alone. METHODS: Six hundred twenty-five postmenopausal women were assigned randomly to one of four treatments, transdermal E2 50 microg/day, or transdermal E2-norethindrone acetate with 50 microg E2 and 140, 250, or 400 microg/day of norethindrone acetate. Follow-up visits to collect information on safety and efficacy were scheduled at 3, 6, 9, and 12 months after initiation of treatment. Endometrial biopsy for histologic evaluation was done at baseline and upon exit from the study (completion or withdrawal). Endometrial histology was evaluated by two independent gynecologic pathologists. In the event of a disparate reading, a third gynecologic pathologist evaluated the tissue using predetermined criteria. RESULTS: Endometrial hyperplasia was found in 37.9% (39 of 103) in the E2 alone group versus 0.8% (one of 123), 1% (one of 98), and 1.1% (one of 89) in the E2-norethindrone acetate 50-140, 50-250, and 50-400 groups, respectively (P < .001). Uterine bleeding was less frequent in the E2-norethindrone acetate 50-140 group than other treatments. The mean number of hot flushes per day decreased to less than one in each treatment group at endpoint. The E2-norethindrone acetate combination patch showed skin tolerance comparable to that of E2 alone. CONCLUSION: Continuous transdermal delivery of E2 combined with norethindrone acetate effectively prevented endometrial hyperplasia in healthy postmenopausal women. Continuous combined transdermal delivery systems provide increased dosing flexibility and might improve convenience and compliance with hormone replacement therapy.

Administration, Cutaneous↗
PubMed2000

Progesterone and follicular changes in postpartum noncyclic dairy cows after treatment with progesterone and estradiol or with progesterone, GnRH, PGF2alpha, and estradiol.

A previous study showed that noncyclic dairy cows treated with 10 microg of GnRH and a progesterone-releasing CIDR insert on Day 0, 25 mg of PGF2alpha and CIDR removal on Day 7, followed by 1 mg estradiol benzoate on Day 9 for those cows that still had not shown estrus (CGPE program) had higher conception rate (47% vs. 29%) than cows treated only with CIDR and estradiol benzoate as above (CE program). This study was to investigate the mechanisms by which the CGPE program improved conception rate compared with the CE program. Sixteen noncyclic Holstein-Friesian cows were randomly assigned to 2 groups balanced for the size and growth pattern of the dominant follicles, which were determined by ultrasonography over a 3-d period. One group received the above CGPE treatment, and the other group received the CE treatment. Follicular and luteal development were monitored by daily ultrasonography. Blood samples were collected daily from Day -2 to Day 11, and thereafter milk samples were collected thrice weekly for a further 24 d. Blood and milk samples were analyzed for progesterone. The GnRH treatment induced ovulation in 7 of 8 cows, resulting in elevated (P<0.05) progesterone concentrations between Days 4 and 7 for cows in the CGPE group. All induced CL underwent luteolysis by 24 h after PGF2alpha treatment. Within 5 d of CIDR removal, 7 of 8 cows in both the CE and CGPE groups ovulated. The interval from emergence of the ovulatory follicle to ovulation was similar (P=0.32) but less (P<0.05) variable for the CGPE group (9.0+/-0.3 d) compared with the CE group (10.3+/-1.2 d). Progesterone concentration in milk samples was similar between the two groups up to 10 d after ovulation. In summary, the GnRH treatment induced ovulation or turnover of dominant follicles, induced a synchronized initiation of a new follicular wave, and increased the progesterone concentration from 4 d after treatment. These could be the reasons for the increased conception rate of cows treated with the CGPE program.

Animals↗