Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen has been shown to modulate angiotensin II (AngII)-regulated behaviors, such as thirst, and may do so by influencing the central renin-angiotensin system (RAS). While numerous studies have attempted to correlate changes in AngII receptors or other components of the RAS with estrogen treatment, the low abundance of these genes has made comparisons difficult. Generally, such experiments have relied on traditional approaches to analyze gene expression that often restrict the experimenter to studying only a few mRNA species, whereas a behavior as complex as thirst may be influenced by changes in multiple genes. The present experiments utilized quantitative receptor autoradiography and mRNA expression profiling to identify and compare AngII receptors and their mRNA levels as well as other components of the RAS in female rat pituitary and hypothalamic-thalamic-septal (HTS) tissue samples. This relatively new approach to the study of gene expression permits the simultaneous comparison of multiple genes from a single tissue sample. These studies revealed that ovariectomized (OVX) female rats treated with estradiol benzoate (EB) had a 30%-40% reduction in the levels of AT(1) receptor mRNA in pituitary and HTS samples as compared to OVX, control animals. In the pituitary, the mRNA levels for angiotensinogen (AGT) were increased by 45% following estrogen administration. In addition, a reduction in [125I]-AngII binding to AT(1) receptors in the pituitary and the subfornical organ was measured following estrogen treatment. These results suggest that estrogen may modulate the pituitary and central RAS through a coordinate regulation of the angiotensin receptors and the levels of newly synthesized AngII.
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PMID:Estrogen decreases hypothalamic angiotensin II AT1 receptor binding and mRNA in the female rat. 1053 59

The pharmacology and pharmacokinetics of drospirenone, a unique progestogen, are reviewed in this paper. Unlike other progestogens, drospirenone, an analogue of spironolactone, has biochemical and pharmacologic profiles similar to endogenous progesterone, especially regarding antimineralocorticoid and antiandrogenic activities. Drospirenone counteracts the estrogen-induced stimulation of the renin-angiotensin-aldosterone system and blocks testosterone from binding to androgen receptors. Because of these characteristics, it has the potential to reduce body weight, blood pressure, and low-density lipoprotein levels and to enhance high-density lipoprotein levels. As a combination oral contraceptive, drospirenone with ethinyl estradiol is effective and has positive effects on weight and lipid levels. Additionally, it relieves menstrually related symptoms (e.g., negative affect and water retention) that are commonly observed with other combination oral contraceptives. Based on the biochemical and pharmacodynamic data, drospirenone appears to be a viable alternative to the currently available progestogens.
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PMID:Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. 1102 26

In the second half of a normal menstrual cycle, progesterone levels rise. Progesterone binds to its specific receptor, but also to the mineralocorticoid receptor; thus progesterone acts as a mineralocorticoid antagonist. For this reason, natriuresis is slightly enhanced in the luteal phase, and, as a reflection of the negative sodium balance, plasma renin and aldosterone rise by 20-50%. This rise is of a compensatory nature, and prevents further sodium losses. All conventional synthetic progestogens, whether they are derivatives of 17alpha-hydroxyprogesterone or 19-nortestosterone, lack the antimineralocorticoid effect of natural progesterone. Ethinylestradiol, as the estrogenic component of combined oral contraceptives, is a sodium-retaining drug. This effect is mainly due to a significant increase of the hepatic synthesis of renin substrate (angiotensinogen). Even with low-dose oral contraceptives, systolic and diastolic blood pressure may be raised in susceptible individuals. Drospirenone is a new progestogen, derived from 17alpha-spirolactone, and the relationship between its progestogenic and its antimineralocorticoid potency is almost identical to that of natural progesterone. In an early preclinical study in 12 normal young women, it was found that the oral administration of 2 mg drospirenone for 6 days led to a cumulative sodium loss of 84 mmol and a significant rise in plasma renin and aldosterone, compared with placebo. In a second experiment, it was found that 2 mg drospirenone given from cycle days 5 to 25 to six regularly menstruating women suppressed ovulation and led to a slight natriuresis without a change in blood pressure, while renin and aldosterone levels slightly increased. The natriuresis and the increase in renin and aldosterone levels did not occur in six other women who received 1 mg cyproterone acetate (a progestogen with antiandrogenic properties), instead of drospirenone. Consequently, an oral contraceptive was designed containing 30 microg ethinylestradiol and 3 mg drospirenone (Yasmin, Schering AG, Berlin, Germany) in the hope of developing a contraceptive that might prevent the sodium retention brought about by the effect of ethinylestradiol. In a 6-month study involving 20 regularly menstruating women, it was shown that the addition of drospirenone to ethinylestradiol did indeed prevent the small rise in body weight and blood pressure observed in some women taking a conventional oral contraceptive. In all studies conducted so far with Yasmin, cycle control and tolerability have been found to be good. In conclusion, Yasmin may become an especially well-tolerated combined oral contraceptive, due to the striking similarity between its progestogenic component drospirenone and progesterone.
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PMID:Drospirenone--a new progestogen with antimineralocorticoid activity, resembling natural progesterone. 1124 98

Increases in blood pressure and weight are consequences of increased fluid retention following oral contraceptives administration. Hypertension and weight increase are particularly frequent in women over 35 years of age. The aim of the present study was to evaluate the clinical and hormonal effects of a new extra-low dose oral contraceptive [15 microg ethinyl estradiol (EE) and 60 microg gestodene (GSD)] on the renin-aldosterone system in a group of women aged 35-39 years treated for 3 months compared with a formulation containing the same hormones at a higher dose. Eighteen healthy women, age 35-39 years, were divided into two groups. The first group (10 women) used Arianna, Schering, 15 microg EE/60 microg GSD (EE15/GSD60); the second group (8 women) used Fedra, Schering, 20 microg EE/75 microg GSD (EE20/GSD75). Blood samples were obtained before the study and after 3 months of contraceptive use for assay of renin and aldosterone. Blood pressure was also measured on both occasions. No significant changes in plasma renin activity (PRA) or plasma concentrations of aldosterone were observed between the two groups after 3 months of contraceptive use. The mean increase in body weight after 3 months of contraceptive use was 350 +/- 100 g for EE20/GSD75 and 300 +/- 50 g for EE15/GSD60. There was a mean increase of 4 mm Hg for systolic pressure and 2 mm Hg for diastolic pressure in women on EE20/GSD75 and corresponding increases of 3 and 2 mm Hg in women on EE15/GSD60. The changes were not significant in any case. The results of the present study show that the formulations were well tolerated and provided good control of the menstrual cycle in all 18 women. The contraceptive formulations EE20/GSD75 and EE15/GSD60 have no clinical impact on blood pressure, PRA, or aldosterone in this age group.
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PMID:Evaluation of plasma levels of renin-aldosterone and blood pressure in women over 35 years treated with new oral contraceptives. 1170 92

Comgination oral contraceptives (OCs) containing ethinyl estradiol 0.05 mg and norethisterone 1 mg is known to cause various metabolic changes and hypertension is 1 of them. Both plasma renin activity (PRA) and angiotensin are considerably increased during pregnancy and these changes are attributed to estrogen induced changes in renin substrate. Recently OCs containing less amount of estrogen are in use and this study reports PRA levels in Indian women taking pills containing 0.03 mg ethinyl estradiol and 1 mg norethistrone. PRA was estimated by radioimmunoassay method in a matched control group and compared with those taking OCs for different durations. Analysis of the data revealed that the mean values for PRA in those taking the low estrogen OC pills were significantly higher than the control group of women not taking the OC.
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PMID:Study of plasma renin activity in Indian women using low estrogen combination pill as contraceptive [abstract]. 1226 90

Phasic oral contraceptives (OCs) provide a physiological approach to contraception and most closely approximate the ideals of a combined OC with the lowest possible doses to avoid the metabolic risks of estrogens and progestins, maximal contraceptive protection, and satisfactory cycle control. Earlier studies have demostrated the decline in myocaridal infarct and thromboembolic disease with reduction of ethinyl estradiol (EE) from 50 to 30 mcg, the correlation between progestin dose and cardiovascular and cerebrovascular deaths, and the effects of progestins derived from 19 nortestosterone in reducing the beneficial high density lipoprotein (HDL) cholesterol. The preparation SH B 264 AB for example provides a 1st phase daily dose of 30 mcg EE and 50 mcg levonorgestrel, a sufficient dosage because of the low probability of ovulation but 1 which attempts to mimic the follicular secretion needed for endometrial growth. Daily doses in the 2nd phase increase to 40 mcg EE and 75 levonorgestrel, each of which is capable alone of inhibiting ovulation. The progestin causes a supplementary hypothalamic inhibition and renders the cervical mucus too viscous for sperm penetration, while the EE augments the hypothalamic inhibitory effect of the progestin, prevents release of luteinizing hormone releasing hormone, and suppresses the luteinizing hormone peak by increasing the pituitary threshold to hypothalamic stimulation. The total dose of SH B 264 AB is at least 30% less than that of other OCs. The Pearl index is 0.0-0.6, not quite as good as that of normal dosed OCs. The duration of menstrual bleeding appears unchanged even after prolonged use, while the amount of bleeding is slightly decreased. Amenorrhea and intermenstrual bleeding are rare. The good cycle control occurs because the steroid levels administered in the triphasic pill mimic those of ovarian secretion, leading to better endometrial development. The effects of triphasic pills on glycemia and insulin levels are very weak and are not statistically significant, while their slight estrogen dominance means that they have very slight effects on the level of HDL cholesterol. They cause a slight increase in triglyceride levels, minimal variation in coagulation parameters, a weak variation in factors VII, VIII, X, and plasminogen, and a slight decrease of antithrombin III. Triphasic OCs induce minimal augmentation in activity of the renin-angiotensin system, and in most cases do not affect blood pressure. Because of their estrogenic dominance, triphasic pills improve acne but may be associated with breast problems, water retention, dysmenorrhea, and premenstrual syndrome with irritability, nervousness, and headache. Triphasic pills are indicated for women beginning OCs, women with poor cycle control under other OCs, women at high cardiovascular risk, women with acne, and women whose current OCs cause oily skin, hirsutism, reduced libido or other symptoms. Contraindications for the triphasic pill in addition to the usual factors include benign breast disease, premenstural syndrome, dysmenorrhea, or polycystic ovarian syndrome.
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PMID:[Pros and cons of triphasic oral contraception]. 1226 12

The role of estrogens in the etiology of vascular accidents was identified soon after oral contraceptives (OCs) came into use over 2 decades ago, but the role of progestins was only identified on the basis of systematic study. Reduction in the estrogen dose of OCs was accompained by a steady decline in venous accidents, but the rate of arterial accidents changed little. It is important to remember that the actual occurrence of vascular accidents in OC users is rare. Available statistics indicate that age and smoking are important risk factors for vascular accidents. Among nonsmokers and smokers respectively, the annual risk of death due to vascular accidents is 1 in 77,000 and 1 in 10,000 for women under 35, 1 in 67,000 and 1 in 2000 for women 35-44, and 1 in 2500 and 1 in 500 for women 45 and over. Some isolated cases of arterial vascular accidents in users of progestin only OCs have been published. The death rate from vascular accidents is 3 times as high when the levonorgestrel dose increases from 150 to 250 mcg, and twice as high when the norethisterone acetate dose increases from 1 to 4 mg. It is not known precisely how synthetic progestins can induce an arterial accident, but the factors involved may include elevation of blood pressure by potentiation of the modifications in renin-angiotensin system caused by ethinyl estradiol, reducing the level of high density lipoprotein (HDL) cholesterol, impairing glucose tolerance, altering the vascular walls directly, or modifying certain coagulation factors. Little data is available on progestin-caused modifications in coagulation factors, but a recent study reported that the effects of combined OCs on coagulation factors increased with the progestin dose. 2 groups of 19-norsteroids are currently used in contraception, the estranes including norethisterone and some prohormones that metabolize to norethisterone before becoming active, and the gonanes including norgestrel, levonorgestrel, and desogestrel. Early optimism concerning a reduced metabolic impact of desogestrel has given way to controversy. The possible unfavorable metabolic effects of progestins are related to their androgenic properties. Observed effects depend on dose level as well as the hormonal balance of the formulation. Pills with an androgenic climate lower the rate of HDL cholesterol while those with an estrogenic climate raise the HDL cholesterol level, which is preferable if it does not entail a simultaneous increase of VLDL or a modification of coagulation factors.
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PMID:[Progestins and arterial disease]. 1228 Feb 5

The main advantage of the triphasic oral contraceptive (OC) is its reduced corticosteroid content, which is accompanied by a reduction in metabolic impact. Triphasic pills differ according to their components and according to whether or not their estrogen dose is constant. The Triella pill has a constant dose of 35 mcg ethinyl estradiol (EE) and a dose of norethisterone that increases from .50 to 1 mg, while Triquilar-Trinordiol mimics the preovulatory estrogen peak while also varying the progestin content. In a study of 22,728 cycles, the Pearl index was only .06/100 woman years for triphasic pills. Comparisons with existing monophasic pills indicate that triphasics may offer improved cycle control, but the fact should be emphasized to patients that cycle control is an inappropriate criterion for choice of pills. Metabolic effects or possible carcinogenic effects are more important qualities. Triphasic pills have been found to improve acne, not to affect weight or blood pressure, and to reduce the frequency of headaches, nervousness, and breast tenderness. Studies have shown that triphasics containing levonorgestrel produce minimal effects on lipid metabolism, while less rigorous studies on triphasics containing norethisterone have also yielded favorable results. It is true however that knowledge of the relationship between alterations in plasma cholesterol caused by Triella use and the etiology of certain diseases remains incomplete. Low dose triphasic pills appear to have fewer deleterious effects on glucose metabolism than higher dose pills, but they are not entirely without effect and should not be prescribed for women at risk of developing diabetes. Studies examining modifications of the intima and coagulation factors have given reassuring results, and neither triphasics with levonorgestrel nor those with norethisterone modify the blood pressure. Triphasics entail a reduction in the levels of estradiol and testosterone and a slight increase of plasma renin activity but no modification in plasma aldosterone. The subtle effects on the gonodotropic axis are considered especially fitting for young women in whom post-pill ovulatory function is preserved. Endometrial biopsies show that the state of the endometrium with OC use is not well understood and highly variable. The triphasic pill approaches as closely as possible the normal physiology of the endometrium while still suppressing ovulation.
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PMID:[The triphasic pill]. 1228 Feb 9

New epidemiologic data on the vascular risks of oral contraceptives (OCs) were assessed to determine whether the recently introduced low dose triphasic pills offer greater potential safety for OC users than previous formulations. Epidemiologic studies have demonstrated that vascular accidents are less frequent with OCs containing lower doses of both estrogens and progestins. The new triphasic pills have the lowest steroid content of any pills yet developed and less of a progestin climate than low dose monophasic pills. The gradual increases in the progestin dose, from 50 mcg on days 1-6 to 75 mcg on days 7-11 and 125 mcg on days 12-21 and of ethinyl estradiol from 30 mcg on days 1-6 to 40 on days 7-11 and back to 30 on days 12-21 reflect the natural cycle of steroid secretion. The endometrial mucus is better developed than under low dose monophasic pills, permitting better cycle control. Triphasic pills have been shown in all studies to block secretion by the hypothalamus and pituitary of the gonadotropins follicle stimulating hormone and luteinizing hormone, resulting in absence of follicular maturation and of ovulation. Even with the small dose of levonorgestrel, the cervical mucus is rendered inhospitable to capacitation and passage of sperm. The impact on glucose tolerance of low doses of ethinyl estradiol, even after long use, is minimal, but the 19 norsteroids used in most combined pills have a more significant impact. To the directly stimulating effect of progestins on pancreatic insulin secretion is added the development of increased peripheral resistence apparently due to a decrease in the number of insulin receptors in the target tissue. The decrease appears to be dose dependent and proportional to the androgenicity of the progestin. A recent study indicated that triphasic pills caused less of a deterioration in glucose tolerance than standard or low-dose combined OCs or a biphasic formulation. This finding was significant because of the possibility that disturbances in carbohydrate metabolism can favor development of vascular diseases. Triphasic OCs have a slight estrogen dominance, which allows them to maintain favorable levels of high density lipoprotein cholesterol, the fraction believed to provide cardiovascular protection. Similarly, they caused minimal variation on the order of 10-15% in the levels of fibrinogen, factors VII, VIII, and X, plasminogen, and antithrombine III. It has not yet been established with certainty however that changes in the levels of these coagulation factors correspond to changes in actual risk of thromboembolic accidents. Triphasics cause a minimal increase in renin substrate and activity of 12-30% compared to the 30-40% at higher estrogen doses. No significant variation in blood pressure has been observed in triphasic OC users.
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PMID:[Potential advantages of triphasic combined oral contraceptives in the light of recent epidemiological and endocrinometabolic data]. 1231 6

Although combined oral contraceptives (OCs) do not create a true cardiovascular risk, they may increase the impact of existing vascular risk factors. Pill use disturbs metabolism of lipids and carbohydrates as well as the balance of water and sodium. New combinations with lower doses of steroids have significantly reduced these risks, and the development of new and less androgenic progestins for low dose pills is expected to reduce them further. The diabetogenic effect of OCs has been noted since 1963. Among normal women, the observed modifications in carbohydrate metabolism are minor and temporary, with increases in levels of blood sugar maximal at the beginning of use and normalizing after 12 months. Among women with family histories of diabetes or who have had gestational diabetes, use of combined OCs can entail irreversible deterioration of glucose tolerance or diabetes. The number of women with poor glucose tolerance increases with the duration of pill use. Reversibility of the condition decreases with duration of use. The proportion of women with poor glucose tolerance who develop diabetes is higher than among normal subjects. Women with poor glucose tolerance must be considered at risk of diabetes. Ethinyl estradiol is responsible for the early modification of glucose tolerance, which regresses after about 6 months of use. Hyperinsulinemia is caused by the direct stimulation of progestins on insulin secretion by the pancreas as well as by the development of peripheral resistence to glucose utilization resulting from a decrease of insulin receptors. The effect on insulin resistence is among the most androgenic progestins. Chronic hyperinsulinism represents a classic risk factor for atherosclerosis because of the effects on the arterial wall: proliferation of smooth muscle fibers, inhibition of lipolysis, and development of lesions of the intima analogous to those of atheroma. Estrogen is primarily responsible for the increased blood pressure of pill users, but the development of hypertension is also correlated with the progestin content. Progestins have an antidiuretic effect which contributes to increases in blood pressure when added to the estrogen stimulation of the renin-aldosterone-angiotensin system. Gestodene, a new progestin in the gonane series, is the most powerful synthetic progesterone yet known. Its uniqueness derives from the dissociation between its very powerful antigonadotropic activity even at small doses and its androgenic effects which only appear at considerably higher doses. Most of the metabolic effects of progestins are linked to their degree of androgenicity. Different studies of gestodene tolerance in a triphasic formulation have concluded that it is innocuous. The use of gestodene in a low-dose triphasic formulation may result in a combined OC that does not increase the individual atheromatous risk of the user.
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PMID:[Combined estrogen-progestagen contraception and glucid and water-sodium metabolism]. 1234 1


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