Mcg Of Estrogen Research Articles

O-044 The future of contraception

Abstract In 1960, the first hormonal contraceptive agent, Enovid approved by the Food and Drug Administration in the United States. The pill contained mestranol 150 mcg and norethynodrel 10 mg. High dose pills containing >50 mcg of estrogen were discontinued in 1988 due to a higher risk of myocardial infraction and stroke secondary to thrombosis. Until recently, the only estrogens used in combination OCPs were mestranol and ethinyl estradiol (EE). Estetrol (E4) and 17-beta estradiol have been added to newer pill and intravaginal ring (IVR) formulations in order to reduce the risk of thrombosis. Progestins confer the primary contraceptive effect in combination agents and can be used without estrogens. First generation progestins include norethynodrel, ethynodiol diacetate, norethindrone and norethindrone acetate (estranes). Second generation progestins include norgestrel and levonorgestrel (gonanes). Third generation include gestoden, desogrestrel and norgestimate, which are less androgen versions of the second generation progestins. Fourth generation progestins have no androgenicity include drospirenone. The fourth generation progestin is a 17 carbon compound which separates it from the other progestins that are primarily 19 carbon derivatives of androgens. Segesterone acetate (SA) is a newer progestin that is less potent and has no androgenic properties. SA, combined with EE, is currently being used in an IVR. However, clinical trials are ongoing using SA with 17-beta estradiol in an IVR and another with EE as a contraceptive gel. Other new methods of hormonal contraception include progestins in a biodegradable implant, longer acting injectables that can last 6-12 months, transdermal patches that are imbedded with an array of microneedles where either the contraceptive agent is in a reservoir or in the needles themselves. Microchip technology is being developed by the Gates Foundation that would allow levonorgestrel to be released systemically at will over a 16-year period using a remote device. Multipurpose technologies are being developed utilizing contraceptive pills, injectables and IVRs containing hormonal agents as well as medications to prevent STI/HIV acquisition.

Ischaemic cerebrovascular disease in young adults. 1. Smoking habits, use of oral contraceptives, relative weight, blood pressure and electrocardiographic findings.

The case histories of all ischemic nonembolic cerebrovascular disease patients under 50 years old seen at the Department of Neurology of the University of Helsinki during 1966-71 were analyzed. The response rate to a detailed questionnaire was very high. 128 men and 85 women comprised the patient population. Cigarette smoking, oral contraceptive use, hypertension, and electrocardiographic abnormalities appeared to be associated with increased risk of cerebrovascular disease. The role played by obesity remained unclear. 78 women provided detailed information about personal oral contraceptive use. 30% of these women and 39% of the 52 women of childbearing age (under 45) had been using oral contraceptives at the time of cerebrovascular accident (CVA). 16% and 20%, respectively, had used oral contraceptives at some time before the accident. 16 women were able to supply the name of the brand used at the time of CVA: 10 (63%) had used pills with estrogen content of 100 mcg and 6 (37%) pills with 50 mcg. On the other hand, in Finland during 1968-1971, only 30% of the pills used contained 100 mcg of estrogen. In the Health Security Area of South Finland (served by the Department), only 15.5% of the women under 45 years of age were oral contraceptors in 1971.

What Practitioners Are Saying When it Comes to the Pills, Patches, Rings and More

Oral contraceptives continue to evolve in an effort to reduce side effects and promote cycle control. The newer combination pills contain lower doses of estrogen (20 to 25 mcg) coupled with various formulations of progestin to enhance cycle control. In Europe a pill with only 15 mcg of estrogen is available. Drospirenone the progestin in Yasmin has antimineralocorticoid properties and acts as a mild diuretic to lessen fluid retention and symptoms of premenstrual syndrome (PMS). Combining etonorgestrel and testosterone to stop sperm production in males is being studied to determine the most effective method for delivery either by injection implant or oral administration. The lower doses of oral contraceptives which provide greater cycle control with fewer side effects are increasingly popular. Methods such as the transdermal patch the vaginal ring and Depo Provera which do not require daily administration are well-suited to todays busy lifestyle and are providing good cycle control with minimal side effects. (excerpt)

Estrogen-priming can enhance progesterone's anti-seizure effects in part by increasing hippocampal levels of allopregnanolone

Estrogen can be proconvulsant, while progesterone and its metabolite allopregnanolone typically have anti-seizure effects. We investigated whether estrogen-priming also has anti-seizure effects by altering progesterone's metabolism to allopregnanolone, or levels of brain-derived neurotrophic factor (BDNF), in the hippocampus. Two experiments investigated effects of different estrogen-priming regimen (Experiment 1—10 μg; Experiment 2—2 μg) on pentylenetetrazole (PTZ)-induced seizures and levels of estrogen, progesterone and allopregnanolone in plasma and hippocampus. In Experiment 1, ovariectomized (ovx) rats were administered sesame oil vehicle or 10 μg 17β-estrogen at hour 0. Forty-four hours later, progesterone (500 μg; SC) or vehicle was administered. At hour 47, PTZ (70 mg/kg IP) was administered. For Experiment 2, a similar protocol was used except that ovx rats were administered vehicle or 2 μg 17β-estradiol at hours 0 and 24. Progesterone, alone or in conjunction with either 10 or 2 μg estrogen-priming, tended to increase the latency to, and significantly reduced the number of, tonic seizures and elevated levels of progestins in hippocampus and plasma. Two, but not 10, micrograms of estrogen alone had anti-seizure effects and increased levels of allopregnanolone in the hippocampus. BDNF levels in the hippocampus were increased by estrogen-priming, but reduced by progesterone administration. Thus, estrogen may have anti-seizure effects by enhancing formation of allopregnanolone.

Estrogen Modulates the Visceromotor Reflex and Responses of Spinal Dorsal Horn Neurons to Colorectal Stimulation in the Rat

Many gastrointestinal pain syndromes are more prevalent in women than men, suggesting a gonadal steroid influence. We characterized the effects of estrogen on two responses to colorectal distention (CRD) in the rat: the visceromotor reflex (vmr) and L6-S1 dorsal horn neuron activity (ABRUPT and SUSTAINED neurons). Ovariectomized rats were injected with estrogen, and responses to innocuous and noxious intensities of CRD were measured between 4 hr and 14 d after injection and compared with ovariectomized and intact, cycling rats. Plasma estrogen levels were determined at each time point. Ovariectomy significantly decreased the magnitude of the vmr and ABRUPT neuron response to CRD compared with cycling rats. Four and 48 hr after estrogen injection (10 microg), the magnitude of the vmr and ABRUPT neuron response returned to the level or greater than that of cycling rats. All responses were comparable with ovariectomized rats by 7 d. These results paralleled the plasma estrogen concentration. Fifty micrograms of estrogen did not further increase the magnitude of the vmr or neuronal response 48 hr after estrogen but did extend the period of the increased ABRUPT neuron response to 14 d. Estrogen did not affect the response of SUSTAINED neurons. In a separate experiment, the response to innocuous CRD was sensitized in estrogen-treated rats but not ovariectomized or cycling rats. The present data suggest that estrogen modulates the spinal cord processing and reflex responses to innocuous and noxious colorectal stimuli in female rats and may contribute to alterations in sensory processing associated with irritable bowel syndrome.

Women with Family History of Breast Cancer Have Added Risk with Pill Use

A multigenerational family study conducted between 1991 and 1996 revealed that women whose sisters or mothers have had breast cancer are at increased risk of developing the disease. The study also suggests that their risk is further elevated if they use oral contraceptives. Overall among sisters and daughters of women with breast cancer those who had ever used the pill had 3.3 times the breast cancer risk of those who had never used this method; the relative risk increased if breast or ovarian cancer occurred more than once among blood relatives. Moreover the elevated risk associated with pill use appeared only among women who had taken oral contraceptives during or before 1975; after that year all oral contraceptives introduced to the market contained less than 50 mcg of estrogen.

Ten Years After Ceasing Pill Use, Former Users Have Mortality Risks Similar to Those of Never-Users

A 25-year follow-up study conducted in the UK has found that increases in mortality associated with the current use of oral contraceptives (OC) do not persist after 10 years of nonuse. Compared with women who have never used the pill current users and women who have used the pill within the previous 10 years are 90% more likely to die from circulatory diseases and more than twice as likely to die from cervical cancer although they are only 20% as likely to die from ovarian cancer. However after 10 years of nonuse former users have mortality levels similar to those among nonusers. The data for this analysis come from 46000 women recruited by their general practitioners in a 1968 study of the health of women taking OCs. Most pill formulations used by women in the study were combined preparations containing 50 mcg of estrogen. Study results are based upon 853517 person-years of experience 517519 contributed by ever-users of OC and 335998 contributed by nonusers.

Topiramate: pharmacokinetics and pharmacodynamics.

Topiramate is a structurally novel anti-epileptic drug with at least 3 postulated mechanisms of action including: 1) potentiation of GABA responses, 2) impairment of AMPA/kainate glutamate receptors and 3) suppression of high frequency action potential firing. It has a favourable pharmacokinetic profile with rapid absorption, good bio-availability, linear pharmacokinetics, relatively long half-life and limited pharmacokinetic drug interactions. However, topiramate can reduce the estrogen component of oral contraceptive medications. Women may require birth control preparations containing 50 micrograms of estrogen. Topiramate clearance is reduced in severe renal failure and increased by enzyme-inducing anti-epileptic drugs. The dose of topiramate may have to be reduced in renal failure or when withdrawing enzyme inducers.

Pill Users' Odds of Stroke are Reduced by Screening for Cardiovascular Risks

A large case-control study conducted at 16 centers in Austria France Germany Switzerland and the UK in 1993-96 estimated that 2-4 strokes/year/100000 women of reproductive age may be attributable to OC use. 220 ischemic stroke patients ages 16-44 years were matched with 775 controls from the same hospital or community. Stroke patients were more likely than controls recruited from hospitals or local communities to smoke (55% vs. 35% and 48% respectively) to have a history of hypertension not associated with pregnancy (16% vs. 6% and 7%) to have diabetes (6% vs. 1% in both types of controls) and to have used OCs in the 3 months preceding stroke diagnosis or study recruitment (58% vs. 30% and 43%). Stroke patients were less likely than controls to consume alcohol frequently (11% vs. 14% and 20%). Logistic regression analysis controlled for age study center cardiovascular risk factors and duration of OC use indicated current OC users were 3.6 times as likely than nonusers to have a stroke. This risk was 4.5 among users of first-generation formulations containing 50 mcg or more of estrogen 3.4 among users of second-generation formulations with less than 50 mcg of estrogen and any progestin other than gestodene or desogestrel and 3.9 among women who used third-generation OCs containing gestodene and desogestrel. Compared with past users of OCs women using second- or third-generation OCs who did not have a blood pressure check before receiving an OC prescription had a 4.5 and 4.6 elevated risk respectively of stroke. This finding confirms the importance of screening for cardiovascular risks and checking blood pressure as a strategy for reducing stroke risk in OC users.

Epidemiology of oral contraceptives and cardiovascular disease.

To review the association between combined oral contraceptives and cardiovascular disease, with emphasis on oral contraceptives containing low doses of estrogen (low-dose oral contraceptives). A systematic search of the MEDLINE database was done for all relevant articles published between 1967 (when low-dose oral contraceptives were introduced in the United States) and June 1997. Textbooks, meeting proceedings, and reference lists were also searched. All English-language human epidemiology studies of oral contraceptives that used cardiovascular disease as an end point were reviewed. Animal and metabolic studies were reviewed only if they were especially relevant to the mechanism of action of oral contraceptives. Descriptive and analytic data from each study were collected. Data were organized by cardiovascular end point, study design, estrogen dose, and type of progestogen. Data on relative and absolute risk are presented to address current prescription guidelines. The risk for cardiovascular disease is lower with current preparations of oral contraceptives, including those that contain the new progestogens, than with older oral contraceptives containing high doses of estrogen. Among users of low-dose oral contraceptives, cardiovascular diseases occur mainly in smokers and women with predisposing factors. Every effort should be made to encourage smoking cessation among potential users of oral contraceptives.

Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy.

Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-microg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200, and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100-400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC(0-24)) values for ethinyl estradiol were 18-30% lower in cycles 2 through 4 compared with cycle 1 (p < or = 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7-33.0% higher (p < or = 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T(max)) values determined during topiramate therapy were not significantly different from those at baseline. When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing > or = 35 microg of ethinyl estradiol.

Coagulation and anticoagulation effects of contraceptive steroids

Epidemiologic data support the notion that first-generation high-dose oral contraceptives (containing > 80 micrograms of estrogen) increased the incidence of thromboembolic events. The quantitative interpretation of these data is difficult because results were often confounded by life-style factors and inadequate diagnostic procedures. With the introduction of modern low-dose combination oral contraceptives, the incidence of thromboembolic events decreased markedly. Although all combined oral contraceptives induce statistically significant changes in hemostatic factors, these changes are generally within normal ranges, and their clinical significance is questionable. Overall, increased activity in hemostatic mechanisms appears to remain in balance. Progestin-only formulations seem to affect hemostatic parameters to a much lesser degree, and their use has not led to an increased risk of thrombosis. Interindividual variations in pharmacokinetics and pharmacodynamics of contraceptive steroids are great and could tentatively explain why certain persons may be at an increased risk of thrombosis. Although most studies have looked at steady-state conditions during contraceptive steroid intake, it would seem prudent to investigate further the hemostatic system during a non-steady-state condition, such as that occurring during the first few days of the pill-free interval.

Contraceptive choices in women with coagulation disorders

When compared with older reports on the thromboembolic effects of high-dose oral contraceptives, new studies with low-dose oral contraceptives have a significantly reduced risk of thromboembolism. In the absence of risk factors such as smoking or inherited disorders predisposing to thrombosis, the modern low-dose oral contraceptive (< 50 micrograms of estrogen) is a safe and effective choice for contraception in women without symptoms who have family histories of sporadic thromboembolism. An intrauterine device or some form of barrier method is recommended for women who have a personal history of venous thrombus disease. The low-dose oral contraceptive may be a good choice in women taking oral anticoagulants because of the risk of teratogenic effects of anticoagulants and the risks of intraperitoneal bleeding associated with ovulation. In addition, oral contraceptives help diminish the excessive menstrual bleeding often seen in these women.

Pill-Associated Strokes Found Less for Low-Dose Than for Higher Dose Pill

Studies conducted in 1960s and 1970s showed that oral contraceptive users are at 4-25 times greater risk of a thromboembolic attack than nonusers. However because the hormone concentrations in oral contraceptives have been reduced over the years a retrospective case-control study reevaluated the association between oral contraceptive use and stroke in 323 Danish women aged 15-44 years who had suffered a cerebral thromboembolic attack. Overall 36% of the stroke patients had been using oral contraceptives. On multivariate analysis users of contraceptives containing 50 mcg of estrogen were at three times the risk of cerebral thromboembolic attack as were nonusers while those who used pills containing 30-40 mcg of estrogen were about twice as likely to have a stroke as were nonusers. A low risk of thromboembolic attack was also found in women who had stopped using the pill. In addition the odds of cerebral thromboembolic attack associated with oral contraceptive use did not change with increasing duration of pill use or with increasing age. Given these findings it is concluded that oral contraceptives are still associated with an increased risk of cerebral thromboembolic attack despite reduction of hormone concentrations.

Risk of Cerebral Thrombosis is Less for Lower Dose Oral Contraceptives than for Higher Dosage Pills

In Denmark 323 15-44 year old women who experienced a cerebral thromboembolism and 1198 age-matched controls completed a questionnaire so a researcher could determine the risk of stroke among women who used oral contraceptive (OC) formulations available in the 1990s. 36% of cases were using an OC at the time of the stroke. 58% of them used an OC brand with 30-40 mcg of estrogen. 6% used a progestin-only OC. The remaining 36% of OC users used an OC brand with 50 mcg of estrogen. These numbers for controls who currently or in the past used an OC were 75% 11% and 14% respectively. The multivariate analysis revealed that users of an OC with 50 mcg of estrogen faced a risk of cerebral thromboembolism 2.9 times that of nonusers. The odds ratio for users of an OC with 30-40 mcg of estrogen was 1.8. It was .9 for users of a progestin-only OC indicating that this OC did not increase the risk of stroke. Past OC users had a lower risk of stroke than did never-users (OR = .5). The risk of stroke did not increase with duration of OC use or increasing age. When the researcher controlled for age OC use and education cigarette-smokers faced a 50% higher risk of stroke than did nonsmokers. The researcher determined that 15% of cerebral thromboembolism cases among fertile women would not have taken place had they never used OCs. These findings showed that the decreased dosage of estrogen reduced the risk of stroke

Epilepsy and pregnancy.

According to a London physician, women with epilepsy taking antiepileptic drugs can take combined oral contraceptives (OCs). It is usual to recommend a combined OC preparation containing at least 50 mcg of estrogen (Ovran) from patients taking enzyme-inducing antiepileptic drugs; this can be increased to 60 mcg by taking 2 30 mcg pills, and if necessary to 80 mcg. To ensure that ovulation is inhibited, the blood progesterone concentration can be measured on day 21 of the 1st cycle. The higher doses of estrogen should be accompanied by higher doses of progestogen. The commonest fetal malformations are cleft lip and palate and congenital heart disease, usually septal defects. These abnormalities may be caused by all the major antiepileptic drugs. Phenytoin has been particularly implicated and may cause minor defects in up to 30% of infants and major defects in about 5%. The incidence of cleft palate and heart defects with phenytoin is 1.8% compared with 0.7% in the general population. With sodium valproate, neural tube defects occur in about 1.5% of pregnancies. Present evidence suggests that carbamazepine is the safest drug. Folic acid supplements reduce the risk of neural tube defects in women at risk, therefore women taking antiepileptic drugs who are contemplating pregnancy should be given a small folic acid supplement or a diet rich in folate. To reduce the risk of bleeding in the perinatal period, pregnant women taking enzyme-inducing antiepileptic drugs should be given oral phytomenadione (vitamin K1) 20 mg daily for at least 1 week before delivery. Vitamin K1 should be given to the newborn immediately after delivery. Only phenobarbitone and primidone might be contraindicated for breast feeding. Mothers with uncontrolled major epilepsy should not be left alone with small children. If there is already 1 sibling with epilepsy the risk of inheriting epileptic liability rises to about 10% and if both parent have epilepsy the risk is 15-20%.

CONTRACEPTION IN WOMEN OLDER THAN 40 YEARS OF AGE

Women older than 40 years have high rates of unwanted pregnancy and abortion and traditionally have had limited choices of contraception agents. In today's market, oral contraceptives should be considered as should IUDs in properly screened candidates. Sterilization is effective for the couple who knows that they will have no more children. Mechanical methods are effective if used when intercourse tends to be a planned event and infrequent. With the variety of agents available in today's market, there is no reason why the unwanted pregnancy rate and abortion rate of the women older than 40 should not be reduced dramatically.

Sub-50 oral contraceptives affect folate kinetics.

The effects of long-term use of oral contraceptives containing less than 50 micrograms of estrogen (sub-50 OCs) on the kinetics of folic acid monoglutamate, vitamin B12 levels, and iron status have been studied in 29 OC users (Marvelon) and in 13 women without OC use serving as controls. At 210 min after oral folate loading the median serum folate concentration was significantly lower in OC users when compared to the control group. OC users showed significantly higher total iron binding capacity and significantly lower serum vitamin B12 concentrations. This data demonstrates that sub-50 OCs significantly affect folate kinetics and vitamin B12 levels. However, the folate and vitamin B12 status does not seem to be at risk.

Oral Contraceptive Estrogen Dose and the Risk of Deep Venous Thromboembolic Disease

Despite the well-recognized association between oral contraceptives and deep venous thromboembolism, little is known about the risks associated with currently marketed formulations containing less than 50 micrograms of estrogen. To assess the venous thrombogenicity of low-estrogen oral contraceptives (those containing less than 50 micrograms of estrogen) relative to intermediate-dose (50 micrograms of estrogen) and high-dose (greater than 50 micrograms of estrogen) formulations, we conducted a cohort study of oral contraceptive users between the ages of 15 and 44 years in the Michigan Medicaid population. The period of the study was from 1980 through the third quarter of 1986. A total of 2,739,400 oral contraceptive prescriptions received by 234,218 women were analyzed. Using the low-estrogen cohort as the referent group, the age and calendar period adjusted relative risk of venous thromboembolism in users of intermediate-dose formulations was 1.5 (95% confidence interval (CI) 1.0-2.1, p = 0.04), and the relative risk in users of high-dose formulations was 1.7 (95% CI 0.9-3.0, p = 0.06). These data provide evidence that the dose-response relation between oral contraceptive estrogen and venous thromboembolism extends from 50 to 30 micrograms of estrogen, the dose range of currently marketed formulations.

Correcting misconceptions about oral contraceptives

Although the majority of American women believe that oral contraceptives can cause serious health problems such as cancer or heart disease, the scientific literature does not support these beliefs. Oral contraceptives actually protect against endometrial and ovarian cancer. The increased incidence of cardiovascular disease in oral contraceptive users, including myocardial infarction, appears to be caused by thrombosis and not atherosclerosis. The studies suggesting an increased risk of cardiovascular disease in oral contraceptive users were published in the late 1970s and therefore used a data base of women ingesting formulations containing 50 micrograms of estrogen or more. More recently published data involving healthy women taking mainly lower estrogen dose preparations suggest that there is no increased incidence of myocardial infarction or stroke. Nearly all published studies indicate that there is no increased risk of myocardial infarction in former users of oral contraceptives. Animal data actually suggest that oral contraceptives may have a protective effect against atherosclerosis, even in the presence of lowered high-density lipoprotein levels. The low-dose triphasic and monophasic formulations are effective, safe methods of contraception that can be used by most healthy women of reproductive age.