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PubMed1996

Identification of genes whose expression is altered during mitosuppression in livers of ethinyl estradiol-treated female rats.

In this study, our goal was to identify genes whose expression in liver is altered in female F-344 rats during mitosuppression induced by 42 days of ethinyl estradiol (EE) treatment (Yager et al., Carcinogenesis, 15, 2117-2123, 1994). Northern analysis demonstrated that the mRNA levels for transforming growth factor-beta1 (TGF-beta1) and the mannose 6-phosphate/insulin-like growth factor II receptor were significantly increased by EE treatment. Ten cDNA clones representing mRNAs whose expression was increased two- to four-fold in the mitosuppressed livers were identified by differential display. Sequence analysis revealed that one was homologous to the S-24 ribosomal protein and another to mitochondrial ATPase subunit e. The remaining clones showed no homology to known genes in GenBank. However, the expression of clones 15, 16 and 17 was increased in HepG2 cells following treatment with doxorubicin suggesting their induction by oxidative DNA damage. These results suggest that two independent but interrelated signalling pathways, one mediated through transforming growth factor-beta and the other through oxidative DNA damage, may contribute to hepatic mitosuppression caused by EE, perhaps through activation of cyclin-dependent kinase inhibitors.

Animals↗

PubMed1980

Comparison of metabolic and clinical effects of four oral contraceptive formulations and a contraceptive vaginal ring.

A group of 100 women desiring OC received one of the following four formulations on a randomized basis: (1) mestranol 50 micrograms and norethindrone 1 mg, , (2) ethinyl estradiol 50 micrograms and norethindrone 1 mg, (3) ethinyl estradiol 35 micrograms and norethindrone 1 mg, and (4) ethinyl estradiol 30 micrograms and levonorgestrel 150 mg. An additional 10 women received a CVR containing levonorgestrel and estradiol. Measurement of a large number of serum chemistries, lipids, proteins, clotting factors, and liver enzymes was obtained before and 3 and 6 months after starting medication. Clinical factors such as weight, blood pressure, bleeding or spotting, or any adverse side effects were also recorded. There was no significant difference in the metabolic parameters measured among the four oral contraceptives except the increase in angiotensinogen was slightly less in the groups receiving the compounds with 30 or 35 micrograms estrogen and the groups receiving the norgestrel compound had no increase in triglycerides and a slight decrease in cholesterol levels. When the CVR was compared with all oral contraceptives it was found to produce no change in angiotensinogen levels and a decrease in triglycerides. Some of each group of OC users had a lowering of antithrombin III to abnormal levels but none of the CVR users had his amount of decrease. As oral steroids with 30 or 35 micrograms of estrogen do not produce significantly less metabolic alteration than do compounds with 50 micrograms of estrogen, it is unlikely that their use will reduce the incidence of the uncommon serious adverse effects associated with OC use. However, since the CVR's did not increase angiotensinogen, their use as contraceptives will most likely not produce hypertension and possibly the other serious circulatory problems which are increased in some OC users.

Adolescent↗

PubMed1992

Ethinyl estradiol-induced cell proliferation in rat liver. Involvement of specific populations of hepatocytes.

Hepatocyte proliferation was analyzed in vivo during the time course of continuous administration to rats of the liver tumor promoter ethinyl estradiol (EE) at 10 p.p.m. in the diet. EE-induced acute liver hyperplasia was detected in male and female Sprague-Dawley rats as an increased mitotic index of hepatocytes after 2 days of treatment. 5'-Bromodeoxyuridine (BrdU) labeling showed that proliferating hepatocytes were randomly distributed throughout the hepatic lobule. Subsequently, and still during the first few days of continuous EE treatment, hepatocyte proliferation decreased to control levels, and a transient increase in the incidence of apoptosis in the liver was detected. Although consistent with the concept of liver growth regression after mitogen-induced hyperplasia, these results differ from others reported to date in that, in our experiments, the cessation of cell proliferation and the subsequent growth regression occurred without withdrawal of EE in our experiments. After returning to control levels, hepatocellular proliferation again increased between 3 and 6 months of chronic treatment and remained activated during the following months of continuous treatment, as seen by accumulative BrdU labeling. Proliferating hepatocytes were predominantly located in zone 2 of the hepatic lobule at this time, surrounding a periportal zone of vacuolated hepatocytes, which were also induced by the treatment. Moreover, hyperplasia of basophilic hepatocytes was also seen around some portal spaces. In another set of experiments, chronic EE-induced activation was characterized by flow cytometry on hepatocytes isolated from male Fischer rats. Ploidy analysis of hepatocyte cell suspensions showed that the normal polyploid pattern of hepatocytes was altered by EE, the proportion of diploid hepatocytes rising considerably. The results also showed that these diploid cells were the most susceptible hepatocyte population to EE-induced proliferation, as shown by a combination of BrdU labeling and cell sorting methods. In contrast to Sprague-Dawley rats, no vacuolated cells were found histologically in the livers of these animals and the proliferating hepatocytes were located adjacent to the portal areas. These results taken together support the existence of cell target populations in the liver responding to the effects of tumor promoters. The finding that a subpopulation of diploid hepatocytes was the liver cell class most susceptible to proliferation during chronic EE treatment may explain, at least in part, the behavior of EE as a tumor promoter in hepatocarcinogenesis.

Animals↗

PubMed1990

Oral contraceptives and coronary artery atherosclerosis of cynomolgus monkeys.

Studies of both human and nonhuman primates show an inverse relationship between high-density lipoprotein (HDL) cholesterol concentrations and coronary artery atherosclerosis. For this reason, there has been concern that the HDL cholesterol-lowering effect of oral contraceptives might exacerbate coronary artery atherosclerosis. We studied three groups of adult female cynomolgus macaques fed a moderately atherogenic diet: a control group, a group given ethinyl estradiol and norgestrel, and another group given ethinyl estradiol and ethynodiol diacetate. Norgestrel and ethynodiol diacetate, co-administered with ethinyl estradiol, lowered the plasma concentrations of HDL cholesterol. However, the extent of coronary artery atherosclerosis was lessened by both contraceptives, especially among females at high risk based on their plasma lipid profiles.

Animals↗

PubMed2005

Combined use of metformin and ethinyl estradiol-cyproterone acetate in polycystic ovary syndrome.

OBJECTIVE: The aim of our study was to compare the effect of metformin applied independently to the effect of metformin used in combination with oral contraceptive containing ethinyl estradiol (EE) and cyproterone acetate (CA). STUDY DESIGN: This prospective, open clinical study lasted 6 months and included 30 women with PCOS, divided in two groups of 15 women each. Group 1 received 850 mg metformin twice a day and group 2 in which Diane35 was added to the same treatment only during the first 2 months of the investigation. Serum levels of testosterone, immune reactive insulin (IRI), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS) and lipid metabolism parameters were measured before the treatment, on the third and sixth month. Free androgen index (FAI) and HOMA-IR were calculated. Body mass index (BMI) and waist-to-hip ratio (WHR) were assessed at baseline and at the end of therapy. RESULTS: Much better and faster decrease in the level of testosterone and free androgen index in group with combined use of metformin and Diane35 was established, without deterioration of the anthropometric and biochemical indices and insulin sensitivity. CONCLUSION: The combination of metformin with intermittent application of Diane35 is an appropriate alternative for the pathogenic influence and clinical improvement of the symptoms of androgen excess in cases with PCOS.

Adult↗

PubMed1988

Lipid and lipoprotein changes associated with oral contraceptive use: a randomized clinical trial.

To determine the effects of oral contraceptives on lipids and lipoproteins over a six-month period, we randomized 266 women into four oral contraceptive groups: ethinyl estradiol 35 micrograms plus ethynodiol diacetate 1 mg, ethinyl estradiol 30 micrograms plus levonorgestrel 0.15 mg, ethinyl estradiol 35 micrograms plus norethindrone 1 mg, and ethinyl estradiol 35 micrograms plus norethindrone 0.5 and 1 mg (biphasic). For all groups, total cholesterol increased 5.9-9.1% from baseline values over the six months. Triglycerides increased with all preparations, with the ethynodiol diacetate group (37.6%) and the biphasic norethindrone group (45.3%) showing the greatest increase. Low-density lipoprotein cholesterol increased 10-15.6% among the groups; low-density lipoprotein-apolipoprotein B changed proportional to the low-density lipoprotein cholesterol increases. All groups except the ethynodiol diacetate group showed a decrease of high-density lipoprotein cholesterol, with the levonorgestrel group (8.7%) and biphasic norethindrone group (4.5%) showing the largest declines. Apolipoprotein A-1 increased in all groups, with the ethynodiol diacetate preparation (19.3%) showing the greatest increase and the levonorgestrel preparation (3.2%) showing the smallest increase from baseline values. The changes in apolipoprotein A-1 were out of proportion to the changes in high-density lipoprotein cholesterol, suggesting that the high-density lipoprotein particle may be undergoing some type of metabolic alteration.

Adult↗

PubMed1997

In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women.

Previous studies with postmenopausal women receiving oral doses of norethisterone-containing preparations have shown that a small fraction of the dose is converted metabolically to ethinyl estradiol and may be detected in the peripheral blood. To investigate the extent and the dose dependence of this conversion in more detail, we performed a study with 24 postmenopausal women who received single oral doses of 5 mg norethisterone as well as 5 and 10 mg norethisterone acetate with a washout phase of 2 weeks between each treatment. After each treatment, blood was collected at regular intervals and the concentrations of norethisterone and ethinyl estradiol were analyzed in the serum samples by a specific radioimmunoassay and by gas chromatography/mass spectrometry, respectively. Ethinyl estradiol was present in the serum samples of all women following treatment with norethisterone acetate and, except for four cases, also after treatment with norethisterone. The conversion ratio of norethisterone acetate to ethinyl estradiol was 0.7 +/- 0.2% and 1.0 +/- 0.4% at doses of 5 and 10 mg, respectively. This corresponded to an oral dose equivalent of about 6 micrograms ethinyl estradiol per milligram of norethisterone acetate. For norethisterone, a conversion ratio of 0.4 +/- 0.4% was found at a dose of 5 mg, which corresponded to an oral dose equivalent of about 4 micrograms ethinyl estradiol per milligram of norethisterone. Although it cannot be excluded that in individual cases, even higher doses of ethinyl estradiol may be produced by conversion, it is concluded that at therapeutic doses of the progestogens, the exposure to metabolically derived ethinyl estradiol is probably of little clinical significance not only in fertile women using oral contraceptive combination preparations containing norethisterone and ethinyl estradiol, but also in postmenopausal women who receive oral doses of estradiol for estrogen replacement. The estrogenic effects of metabolically derived ethinyl estradiol on the liver (eg. synthesis of transport proteins) are very likely more than compensated due to the androgenic activity of norethisterone.

Administration, Oral↗

PubMed1980

Spontaneous reversal of ethinyl estradiol-induced cholestasis in the rat.

The spontaneous reversal ethinyl estradiol-induced cholestasis has been documented 7 days after the last estrogen administration in the rat. This finding supports the hypothesis that estrogens produce only a transient functional failure of the hepatocytic structures responsible for bile secretion.

Animals↗

PubMed2000

Impact of subdermal norgestrel on hepatic acyl-coenzyme A:cholesterol- acyltransferase (ACAT) activity: possible antiatherogenic effect.

The impact of subdermally placed ethinyl estradiol, norgestrel, and the combination of the two on cholesterol metabolism as measured by hepatic acyl:cholesterol-acyltransferase (ACAT) activity was examined in the rat model. A total of 48 rats were assigned to one of 6 groups, receiving either 0.1 mg or 1.0 mg of ethinyl estradiol daily, 1.0 or 10 mg of norgestrel daily, and combinations of either 0.1 mg ethinyl estradiol/1.0 mg norgestrel or 1.0 mg ethinyl estradiol/10 mg norgestrel daily. All drugs were administered through subdermally placed time release capsules. The administration of norgestrel only in either 1.0 mg or 10 mg resulted in significantly lower rates of ACAT activity (0.77 +/- 0.566 and 0.91 +/- 0.239 pmol/mg/min, respectively). The combination of 1.0 ethinyl estradiol and 10 mg norgestrel resulted in a significant increase in ACAT activity to 2.17 +/- 0.873. This combination also resulted in significantly greater weight loss at the conclusion of treatment [247.83 +/- 6.2 g (pre) vs. 205.50 +/- 10.6 (post)]. There were no other differences in ACAT activity between groups and no other differences in weight, both between groups and pre- and post-treatment within groups. In summary, subdermally placed norgestrel resulted in a significant lowering of ACAT activity not seen with either administration of ethinyl estradiol alone or the combination of ethinyl estradiol and norgestrel in doses ranging from 0.1 to 1.0 mg of ethinyl estradiol and 1.0 to 10.0 mg of norgestrel. Significantly increased ACAT activity for the combination of 1.0 ethinyl estradiol and 10 mg norgestrel over either ethinyl estradiol or norgestrel alone or a lower dose combination suggests a dose-related threshold and drug-drug interaction for this effect. These results suggest that subdermally placed norgestrel may result in significantly lower ACAT activity and may have a potential role as an antiatherogenic treatment.

Administration, Cutaneous↗

PubMed1982

Circadian pattern of prolactin secretion in postmenopausal women receiving estrogen with or without progestin.

The circadian rhythm of prolactin secretion was assessed in postmenopausal women before and after daily administration of ethinyl estradiol for 4 weeks given in the morning (AM) or evening (PM) or in combination with a synthetic progestin, 17-medroxyprogesterone acetate. In response to AM ethinyl estradiol, mean circulating levels of serum prolactin during sleep and awake phases of the day rose 2.5-fold compared to untreated control values. The sleep/wake ratios for serum prolactin were comparable prior to and after AM administration of ethinyl estradiol. Altered time of administration, PM ethinyl estradiol or concomitant ethinyl estradiol and progestin treatment produced similar increases in mean prolactin levels, which were not different from the level observed during AM administration of ethinyl estradiol. These findings indicate that estrogen replacement therapy, in a dosage recommended for treatment of the menopause, stimulated a sustained rise in serum prolactin over 24 hours. This enhanced release of prolactin was not influenced by the time of administration of estrogen or concomitant administration of 17-medroxyprogesterone acetate.

Circadian Rhythm↗

PubMed1991

Hirsutism: metabolic effects of two commonly used oral contraceptives and spironolactone.

Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

Analysis of Variance↗

PubMed1990

Effect of low-dose oral contraceptives on carbohydrate and lipid metabolism in women with recent gestational diabetes: results of a controlled, randomized, prospective study.

Women with recent gestational diabetes mellitus were randomly assigned to one of two low-dose oral contraceptives to evaluate the effect of low-dose oral contraceptives on carbohydrate and lipid metabolism. A cohort of similar women requesting a non-oral-contraceptive method served as controls. The two oral contraceptives studied were ethinyl estradiol (0.035 mg)-norethindrone (0.40 mg) and ethinyl estradiol (0.030 to 0.040 mg)-levonorgestrel (0.050 to 0.125 mg). A 75 gm, 2-hour oral glucose tolerance test and a fasting lipid profile (total cholesterol, triglyceride, high- and low-density lipoprotein cholesterols) were performed at entry, after 3 months, and after 6 to 13 months of treatment. The prevalence of diabetes at 6 to 13 months (27/156 patients) was not significantly different between groups (non-oral-contraceptive group, 17%; ethinyl estradiol-norethindrone, 15%; ethinyl estradiol-levonorgestrel, 20%). When examined by prior gestational diabetes mellitus class, diabetes mellitus was present in 7% of prior class A1 and 29% of women with prior class A2 disease (p less than 0.001). Mean cholesterol and low-density lipoprotein cholesterol levels were significantly improved in all three groups at 3 months and at 6 to 13 months, whereas triglycerides remained unchanged. There were no differences in cholesterol, low-density lipoprotein cholesterol, or triglycerides levels between the groups. After 6 to 13 months, there was a significant increase in high-density lipoprotein cholesterol in the ethinyl estradiol-norethindrone group compared with the ethinyl estradiol-levonorgestrel and non-oral-contraceptive groups.

Adult↗

PubMed2004

Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women.

BACKGROUND: Several antiepileptic drugs have clinically significant pharmacokinetic interactions with oral contraceptives (OCs) that may result in contraceptive failure. OBJECTIVE: The aim of this study was to assess the effect of zonisamide on the pharmacokinetics of the individual components of a combination OC (ethinyl estradiol [EE] 0.035 mg and norethindrone [NOR] 1 mg) and on pharmacodynamic variables that may be increased in the event of reduced contraceptive efficacy (concentrations of serum luteinizing hormone [LH], follicle-stimulating hormone [FSH], and progesterone). METHODS: This was a single-center, open-label, 1-sequence, crossover study. Healthy, premenopausal women received the combination OC for three 28-day cycles (combination OC for 21 days, followed by placebo for 7 days). Following stabilization on the OC during the first cycle, blood was collected during cycle 2 for the determination of serum EE and NOR profiles (day 14) and serum LH, FSH, and progesterone concentrations (days 13-15). Starting on day 15 of cycle 2, zonisamide was administered orally at 100 mg/d and titrated to a target dose of 400 mg/d. EE and NOR profiles and serum LH, FSH, and progesterone concentrations were obtained again in cycle 3 (in the presence of zonisamide) and compared with those from cycle 2 (in the absence of zonisamide). RESULTS: Thirty-seven healthy premenopausal women (mean age, 26.1 years [range, 18-51 years]; mean body weight, 65.5 kg [range, 50.4-93.1 kg]; mean height, 165.8 cm [range, 152.4-182.9 cm]) received > or =1 dose of zonisamide. Of the 33 subjects (89.2%) who completed the study, 26 (78.8%) underwent titration to a stable zonisamide dose of 400 mg/d. For EE, the mean (SD) AUC over a 24-hour dosing interval (AUC(tau)) was 1139 (317) pg.h/mL in cycle 2 and 1143 (312) pg.h/mL in cycle 3; the mean C(max) in the respective cycles was 133 (39) and 141 (46) pg/mL. For NOR, the corresponding values were 140 (48) and 159 (46) ng.h/mL for AUC(tau) and 21 (5.4) and 23 (6.7) ng/mL for C(max). The 90% Cls for the geometric mean ratios (cycle 3:cycle 2) for AUC(tau) and C(max) fell within the accepted range for lack of interaction (0.80-1.25). There were no increases in LH, FSH, or progesterone concentrations between cycle 2 and cycle 3. CONCLUSIONS: In these healthy volunteers, steady-state zonisamide dosing had no clinically significant effect on the pharmacokinetics of EE or NOR. There was no pharmacodynamic evidence that zonisamide is likely to reduce the contraceptive effectiveness of OCs containing EE and NOR.

Adult↗

PubMed1999

"Estrophasic" dosing: A new concept in oral contraceptive therapy.

The first of a new "estrophasic" type of oral contraceptive with 20 microg ethinyl estradiol on cycle days 1 through 5, 30 microg ethinyl estradiol on days 6 through 12, and 35 microg ethinyl estradiol on days 13 through 21 and 1 mg norethindrone acetate throughout the cycle (Estrostep; Parke-Davis, Morris Plains, NJ) combines a continuous low progestin dose with a low, gradually increasing estrogen dose. It was developed to ensure good cycle control while conferring the benefits of low hormone content, such as minimizing estrogen-related side effects. In a double-blind, randomized, parallel-group trial, Estrostep provided acceptable cycle control and excellent tolerableness, comparable to that of the 30-microg ethinyl estradiol monophasic control drug. In a second study Estrostep demonstrated a neutral impact on serum lipids, like the triphasic control drug. This new oral contraceptive design offers a useful low-dose alternative to existing combination preparations.

Adolescent↗

PubMed1990

Effect of estrogens on prolactin secretion in transsexual subjects.

The effect of estrogens on the secretion of prolactin in 8 different groups of transsexual subjects was studied. Two different types of estrogens, estradiol or its conjugate and ethinyl estradiol, were used. Different doses and durations of exposure were employed. Plasma levels of prolactin and SHBG after estrogen exposure were compared with corresponding levels before treatment. Results showed that for estrogens to exert an enhancing effect on the secretion of prolactin, three factors needed to be considered: (i) the absolute concentration of estrogen, (ii) the duration of exposure, and (iii) whether levels of SHBG are sufficiently altered to change the concentration of free estrogen. It appears that there exist both time and dose thresholds for effective enhancement of prolactin secretion by estrogen. Estradiol and its conjugate are more likely to induce hyperprolactinemia than ethinyl estradiol. The reduced effect of the latter is probably related to its ability to induce large and rapid increases in SHBG binding which probably results in unaltered free estrogen concentration. In the light of this study, treatment of male transsexuals with high doses of estradiol in its conjugate forms must be viewed with caution.

Adult↗

PubMed2004

Oral contraceptive use and breast cancer risk: modification by NAD(P)H:quinone oxoreductase (NQO1) genetic polymorphisms.

Despite intensive study, the relationship between oral contraception (OC) and breast cancer remains unclear. OCs contain a potent synthetic estrogen (ethinyl estradiol) but lower endogenous estradiol levels, and ethinyl estradiol is a weak progenitor of semiquinones, catechol estrogens capable of damaging DNA. NAD(P)H:quinone oxoreductase (NQO1) stabilizes semiquinones, thus potentially preventing genetic damage from catechol estrogens, and the NQO1 C609T polymorphism seems functionally relevant. Using data from the Shanghai Breast Cancer Study, a population-based case-control study, we investigated the relationships between OC use (20% ever using), breast cancer, and NQO1 (C/C 31% and C/T + T/T 69%) among 1,039 cases and 1,121 controls. Breast cancer was not significantly associated with NQO1 genotype. There was a significant protective association between OC after age 30 years and premenopausal breast cancer [odds ratio (OR) 0.51, 95% confidence interval (95% CI) 0.29-0.89] primarily with the NQO1 T allele (C/C OR 0.76, 95% CI 0.31-1.82; C/T + T/T OR 0.38, 95% CI 0.18-0.80; P for interaction = 0.19). The association between premenopausal breast cancer and OCs significantly differed with NQO1 genotype when using OCs for >18 months (C/C OR 2.34, 95% CI 0.92-5.99; C/T + T/T OR 0.69, 95% CI 0.38-1.25; P for interaction = 0.02). Among women with the C/C genotype, postmenopausal breast cancer was significantly associated with ever-using OCs (C/C OR 2.01, 95% CI 1.08-3.74; C/T + T/T OR 0.72, 95% CI 0.49-1.05; P for interaction < 0.01). This crossover was stronger with OC use prior to age 30 years (C/C OR 3.00, 95% CI 1.43-6.25; C/T or T/T OR 0.49, 95% CI 0.29-0.81; P for interaction < 0.01). Our results require confirmation but suggest that the OC and breast cancer association depends on the ability to invoke protection from catechol estrogens.

Adult↗

PubMedDate not supplied

Modulation by S-adenosyl-L-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis.

Structural and functional changes in the surface membranes of hepatocytes play a pivotal role in the induction and reversion of some forms of drug-induced cholestasis. To elucidate the mechanism by which S-adenosyl-L-methionine (SAMe) leads to a partial reversion of bile flow impairment caused by ethinyl estradiol (EE), female Sprague-Dawley rats were given oral doses of EE (5 mg per kg per day, for 3 days) with and without simultaneous administration of SAMe (25 mg per kg, 3 times per day, for 3 days). Na+,K+-ATPase activity and membrane microviscosity as measured by fluorescent polarization were assayed in isolated liver plasma membranes (LPMs). SAMe administration to normal and EE-treated rats resulted in a marked increase in Na+,K+-ATPase activity and LPM fluidity. EE alone did not cause any change in the physicochemical properties of the LPMs. Hepatic Mg2+-ATPase and gamma-glutamyl transpeptidase activities were not affected by SAMe alone but increased when SAMe was given together with EE. These data indicate that the interaction of in vivo administered SAMe with hepatocyte plasmalemma and its effect on lipid fluidity and enzymes of the LPMs showed a high specificity and an inverse relationship between Na+,K+-ATPase activity and fluorescence polarization values. Furthermore, modulation of hepatic Na+,K+-ATPase was associated with SAMe-induced protection against bile flow impairment due to EE; however, it was not the causative factor for EE-induced cholestasis under the experimental conditions. These findings suggest that changes in surface membrane structure and function might account in part for the reversal by SAMe of EE-induced impairment of bile secretory function.

Animals↗

PubMed2001

Influence of two low-dose oral contraceptives on pulsatile gonadotropin secretion.

In this study, we investigated the influence of two combined oral contraceptives on pituitary gonadotropin secretion and their pulsatile characteristics. The contraceptives compared were 30 micrograms ethinyl estradiol plus 125 micrograms levonorgestrel; and 20 micrograms ethinyl estradiol plus 150 micrograms desogestrel. In 13 healthy normocyclic women, hormonal patterns were obtained in the early follicular phase (EFP) and mid-luteal phase (MLP) of an ovulatory control cycle, and on day 5/6 and day 20/21 of the first treatment cycle during a 12-hour period of continuous blood sampling. On the fifth day of treatment, both combinations had significantly suppressed the mean levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The LH pulse frequency of the treatment cycle was significantly inhibited in comparison with the EFP of the control cycle. While increased LH pulse amplitudes were observed on treatment day 5 for both combinations, only the effects of the levonorgestrel-containing combination were found to be significant. In all volunteers, ovulation was reliably inhibited during the treatment cycle, which was indicated by very low progesterone levels. Estradiol secretion was also suppressed on treatment day 21. It is concluded that: (1) the pulsatile character of gonadotropin secretion is maintained at a low level during treatment with low-dose contraceptives; (2) the effects of the monophasic combinations on gonadotropin pulsatility do not seem to depend on the amount of ethinyl estradiol they contain.

Adult↗