Progestogens In Oral Contraceptives Research Articles

Oral contraceptives and venous thromboembolism: identifying the safest option

Evaluation of: van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case–control study. BMJ 339, b2921 (2009).Women who use combined oral contraceptives containing estrogen and progestogen have an associated two- to eight-fold increased risk of venous thromboembolism. Over the years, in an attempt to reduce the associated venous thrombotic risk, newer preparations of oral contraceptives containing lower doses of estrogen and different types of progestogens have been introduced. The article under evaluation has quantified and further examined this association according to the dose of estrogen and the type of progestogen in oral contraceptives, in a large cohort of premenopausal women in The Netherlands. The results showed that oral contraceptive preparations that contain levonorgestrel and those that contain a low-dose estrogen were associated with lower risk than preparations containing other types of progestogens (including newer preparations, such as cyproterone acetate and drospirenone) and a greater estrogen dose, respectively.

Inhibitory effects of progestogens on the estrogen stimulation of melanocytes in vitro

Background The use of oral estrogen–progestogen contraceptives may cause melasma, an epidermal hyperpigmentation in sun-exposed areas of the face. It is assumed that elevated estrogen levels lead to the activation of melanocytes, while the role of the gestagen component of contraceptives in pigmentation remains unclear and may vary between the different progestogens. In this study, we analyzed the distinct effects of progesterone and chlormadinone acetate (CMA) on melanocytes in comparison with estrogen. Study Design Human melanocytes were exposed to different concentrations of 17β-estradiol and progestogens and analyzed for proliferation by a fluorometric cell viability assay and for pigmentation by a 3H-labeled tyrosine assay. Subgroups of cells were additionally irradiated with UVA or UVB. Results Proliferation of melanocytes was induced by 17β-estradiol (0.1 and 1 nM) in approximately half of the experiments, while progesterone (100 nM) and CMA (100 nM) reduced the proliferation rate by 38% and 27%, respectively. The pigmentation activity was slightly stimulated by 17β-estradiol, whereas progestogens had no effect on the tyrosinase activity. Conclusions Our data suggest that progesterone and CMA can inhibit proliferation of human melanocytes, which counteracts the stimulatory effects of estrogen. This may be of relevance for the choice of progestogen in oral contraceptives to prevent the development of melasma.

Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives.

Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P < 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1&2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.

Hormonal contraception and substitution therapy: the importance of progestogen for cardiovascular diseases

Epidemiological data have demonstrated, that the progestogen component of oral contraceptives is involved in the development of hypertension, ischaemic heart diseases and stroke. It had been suggested, that atherosclerotic lesions due to the unfavourable effect on lipid metabolism of progestogens with androgenic properties, play a causal role. It has, however, been shown, that there is no development of atherosclerosis despite reduced HDL and elevated LDL, presumably because of the induction of hepatic LDL- and remnant-receptors by the strong effect of ethinyl-oestradiol upon the liver. A series of experimental and clinical findings indicates that vasospasms caused by the vasoconstrictory effect of progestogens are involved in the development of arterial thromboses. In postmenopausal women, the additional administration of progestogens to the oestrogen treatment may trigger ischaemic diseases, particularly in the presence of vascular lesions. Oestrogens exercise a pronounced vasodilatory effect and stabilize the vascular tonus--through changes in the responsiveness of endothelium and smooth muscle cells to vasoactive compounds, through modulation of neurotransmitter release from nerve endings, and through direct blocking of calcium channels. The effects depend essentially on an intact endothelium. By a direct action on the vascular wall, progestogens increase the sensitivity of arteries to vasoconstrictory compounds and reduce blood flow. As aldosterone increases the number of beta-adrenergic receptors in the arterial smooth muscle cells and thus act vasodilatorily, it cannot be excluded, that progestogens with high affinity to the aldosterone receptor and antimineralocorticoid properties, may exert a strong vasoconstrictory effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Haemorheological consequences of oestrogen and progestogen therapy

A clinical investigation was undertaken of the haemorheological effects of short-term administration of synthetic sex hormones. In a randomised controlled investigative trial, groups of 20 women taking ethynyloestradiol, norethisterone, combined norgestrel and ethynyloestradiol or no therapy had their blood viscosity and its major determinants measured before and after 3 months of treatment. Oestrogens and progestogens, singly or in combination, were found to cause a rise in blood viscosity. Oestrogens did so by raising haematocrit and plasma fibrinogen, parameters that are similarly raised in other conditions such as pregnancy and following surgery when venous thromboembolism is common. The synthetic progestogen, on the other hand, raised the blood viscosity by increasing the haematocrit and decreasing erythrocyte deformability, parameters that are similarily altered in occlusive arterial disease. The combined preparation raised blood viscosity by altering all three parameters. These observations indicate the pathways whereby various synthetic oestrogens and progestogens in oral contraceptives or replacement therapy may be associated with different types of cardiovascular pathology.

The Biochemistry of Oral Contraceptive Steroids

As a prelude to an explanation of the mode of action of modern oral contraceptives a review of the structure biologic activity receptor binding pharmacokinetics and biologic effects of estrogens and progestogens in oral contraceptives is presented. Biologic activity of sex steroids is defined by results of bioassays and the efficacy potency and toxicity may vary between different species and when combined with other agents. Steroids act by binding to specific target cell receptors that also possess specific binding sites for specific regions of the cell DNA. Bioavailability of the steroids is largely determined by plasma concentrations. The chemical structure of the steroids influences both receptor binding and bioavailability profoundly. Estrogens include natural steroids certain nonsteroid plant isoflavones totally unrelated synthetic estrogens and synthetic steroid esters. Progestins used pharmacologically may be structurally related to testosterone (norgestrel norethindrone) or progesterone (megestrol acetate). In combined oral contraceptives the estrogen works by inhibiting tonic gonadotropin secretion (FSH) in the beginning of the cycle so that no dominant follicle matures. Without a follicle to secrete estradiol no LH surge occurs to stimulate release of an oocyte. Progestins also act to inhibit LH. Pills counter other processes to decrease the chance of pregnancy such as maturation of the endometrium. The synthetic anti-progestin RU-486 also inhibits development of follicles in women when endogenous progesterone levels are low an example of agonist-antagonist activity.

New progestogens in oral contraceptives

International Journal of Gynecology & ObstetricsVolume 27, Issue 2 p. 318-318 Citations from the literature endocrinology New progestogens in oral contraceptives B Runnebaum, B RunnebaumSearch for more papers by this authorT Rabe, T RabeSearch for more papers by this author B Runnebaum, B RunnebaumSearch for more papers by this authorT Rabe, T RabeSearch for more papers by this author First published: October 1988 https://doi.org/10.1016/0020-7292(88)90076-8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume27, Issue2October 1988Pages 318-318 RelatedInformation

New progestogens in oral contraceptives

The aim of using new synthetic progestogens (gestodene and norgestimate) in oral hormonal contraceptives is to find a combination that has a more beneficial effect on metabolism and endometrium than presently available formulations. Our studies with low-dose pills containing 30 micrograms ethinyl estradiol/150 micrograms levonorgestrel or 30 micrograms ethinyl estradiol/150 micrograms desogestrel compared with the new pills with 35 micrograms ethinyl estradiol/250 micrograms norgestimate or 30 micrograms ethinyl estradiol/75 micrograms gestodene revealed no significant alterations of serum glucose after glucose loading. With all four combination pills, insulin levels were slightly elevated when compared with controls. Studies of the lipid metabolism showed that depending on the type and estrogen combination, progestogens have different effects on lipid metabolism. The new progestogens seem to have a more pronounced effect on triglycerides, whereas total cholesterol and high-density lipoprotein cholesterol remain almost unchanged. In general, it could be shown that low-dose oral contraceptives have little impact on lipid metabolism. Studies with low-dose monophasic preparations, including the new formulations, reveal only a low effect on blood coagulation. According to our and other data on the new progestogens in oral contraceptives available so far, it can be expected that such low-dose monophasic and triphasic combination pills will be beneficial during longtime use with respect to side effects on the cardiovascular system and control of the menstrual cycle.

Evaluation of a new triphasic oral contraceptive in private practice

We evaluated the clinical and metabolic effects of a new triphasic regimen developed in the continuing attempt to reduce the dose of estrogen and progestogen in oral contraceptives. A combination of ethinyl estradiol (EE) and levonorgestrel (LNg) was used (six tablets with 30 μg EE + 50 μg LNg, five tablets with 40 μg EE + 75 μg LNg, and 10 tablets with 30 μg EE + 125 μg LNg), also known as Triphasil ® (Wyeth). In a private practice, 409 subjects participated in 7,286 treatment cycles. Three pregnancies occurred, all due to subject failure. Menstrual regulation was excellent and the incidence of side effects extremely low. Withdrawals from the study for possibly drug-related medical reasons totaled 9.0% through 56 cycles of treatment. Metabolic changes also were evaluated in 14 of these women over a 6-month period. The only statistically significant increase in carbohydrate values occurred at 6 months. The mean glucose level at 30 minutes of the oral glucose tolerance test was above the baseline mean value, but serum insulin levels showed no statistically significant deviation. Lipid values presented are total lipids, total cholesterol, triglycerides, α-, β-, and pre-β-lipoproteins, and high density and low density lipoprotein cholesterol. There was no statistically significant difference between the mean values at baseline and those during treatment for any lipid variable. These results indicate that this triphasic oral contraceptive has a high degree of efficacy, a low incidence of side effects, excellent cycle control, and high subject compliance, and would seem to indicate a minimal influence on the metabolism of lipids and carbohydrates in the small number of subjects studied.

Structure elucidation of two isomeric steroids: photolytical and thermal reaction products from norethisterone studied by two-dimensional nuclear magnetic resonance.

Two-dimensional nuclear magnetic resonance was used for the structure elucidation of two isomeric photoproducts of norethisterone, a commonly used progestogen in oral contraceptives. The predominant one of the two isolated products derived from photochemical decomposition of norethisterone upon irradiation with UV-B light (280-320 nm) was 5 alpha, 17 beta-dihydroxy-19-nor-17 alpha-pregn-20-yn-3-one. The minor photoproduct appeared to be the analogous 5 beta-isomer, i.e. 5 beta, 17 beta-dihydroxy-19-nor-17 alpha-pregn-20-yn-3-one. The latter compound was also obtained from the thermal reduction of norethisterone-4 beta, 5 beta-epoxide using aluminium amalgam in isopropanol. Two-dimensional NMR appeared to be superior to mass and IR spectrometry in identifying the isomers.

Pharmacodynamic studies on desogestrel administered alone and in combination with ethinylestradiol.

Most progestogens in oral contraceptives are testosterone derivatives and have androgenic side effects such as weight increase, acne and hirsutism. They pose a problem to many women just like the clinical picture of the polycystic ovary syndrome (PCO) with obesity, hirsutism, acne and amenorrhea. The aim of this study was to evaluate androgenicity of the most used progestogens with special reference to desogestrel which is a new progestogen. Radioimmunoassay was used for hormone determination while serum proteins were determined with electroimmunoassay or in some studies for sex hormone binding globulin (SHBG) with capacity assays. Serum lipids and lipoproteins were determined in serum and after ultracentrifugation in HDL, LDL and VLDL fractions. In a comparative study on levonorgestrel/ethinylestradiol (EE) (n = 10) versus desogestrel/ethinylestradiol (n = 10) the latter combination gave increases in SHBG capacity while the former did not. Similar increases in estrogen-sensitive proteins cortisol binding globulin (CBG) and ceruloplasmin indicated that the estrogenicity and "antiestrogenicity" was the same for the two combinations whereas the androgenicity of levonorgestrel was greater giving a reduction in the EE-induced increase in SHBG (SHBG is increased by estrogens and suppressed by androgens). When giving desogestrel 0.125-0.500 mg and lynestrenol 5 mg alone in daily doses to a group of regularly menstruating women (n = 8) strong suppression of SHBG was achieved while ceruloplasmin, CBG and thyroxine binding globulin (TBG) did not change. TBG is decreased and prealbumin increased by androgenic/anabolic activity but only a moderate increase in prealbumin was found during lynestrenol treatment. The changes in SHBG are probably the result of a dose-dependent receptor interaction related to 17 alpha-alkylation in 19-norsteroids. Twenty women with PCO were treated for 8 months with 0.150 mg desogestrel/0.030 mg EE. Evaluation was done before treatment and after 3 and 8 "pill" cycles regarding androgens, estradiol, SHBG, hirsutism and body weight. Spontaneous menstrual cycles were assessed after treatment. Serum lipids and lipoproteins were studied before treatment and at the end of the third "cycle". In PCO the suppression of increased total and free testosterone levels (in comparison to 22 healthy women) was evident during treatment, concordant with increases in SHBG capacity. Hirsutism was suppressed and body weight was reduced in obese women.(ABSTRACT TRUNCATED AT 400 WORDS)

Potency of progestogens in oral contraceptives -- Further Delay of Menses data

The original Delay of Menses Test was designed to provide a guide to suitable starting dosages in formulating new contraceptives. The ability of progestogens to maintain uterine hemostasis was measured and a potency relationship among progestogens was predicated. No delay of menses data previously reported have related to tests of progestogens combined with the same dose of estrogen as used in current oral contraceptives. The Delay of Menses Test was repeated using a standardized dose of ethinyl estradiol and doses of four progestogens each found in combination with EE as marketed oral contraceptives. New and more meaningful relative potencies were derived.

A perspective on progestogens in oral contraceptives

Steroid contraception was developed in the late 1950s and introduced into use in the early 1960s. It soon became apparent that estroprogestational agents had adverse systemic effects, mainly on the cardiovascular and blood coagulation system. During the 1970s, new contraceptive agents were developed that contained 30 to 50 mcg of estrogen. Despite the low amount of estrogen it was clear that vascular side effects persisted. Progestogen-only oral contraceptives or the newest type of contraceptives, also produce side effects, such as elevation of the blood pressure, alterations in serum lipids, elevation of blood glucose and plasma insulin; these effects may accelerate atherogenesis. New studies in steroid contraception will focus on lowering the doses of progestogen components in contraceptive preparations.

Clinical pharmacology and common minor side effects of oral contraceptives.

Attention in this discussion of clinical pharmacology and common minor side effects of oral contraceptives (OCs) is directed to the following: preparations available; the pharmacokinetics of contraceptive steroids (estrogens and progestogens); the clinical implications of altered pharmacokinetics; the choice of an initial OC; and the common minor side-effects of nausea/vomiting breakthrough bleeding absence of withdrawal bleeding depression and weight change. Over 2 dozen OCs are currently marketed in the United States and the majority are modifications of the 1st generation combined estrogen/progestogen formulation. It seems obvious that too many preparations are available to the clinician who is inundated with information from their manufacturers. There is little difference in the ability of the various preparations to prevent pregnancy. Much confusion continues to exist regarding the pharmacokinetics of contraceptive steroids. The clinical implications of pharmokinetic differences in various populations the effects of diet disease states and interactions with other drugs have only recently received attention. Mestranol (ME) and ethinyl estradiol (EE) seem to be well absorbed since the majority (60%) of an orally administered dose can be recovered in the urine. In the human ME is demethylated to EE. Ethinyl estradiol undergoes enterohepatic recirculation and reabsorption. Mestranol and EE peak concentrations occur within 1-2 hours after oral administration. There are 5 oral contraceptive progestogens used commercially in the United States. These steroids are 19-nortestosterone compounds that exhibit progesterone-like activity and are used because progesterone itself is inactive when administered orally. Over 30 metabolites have been identified for the various progestogens and the major pathways are outlined. Many factors such asdrugs diseases and pharmacogenetics are believed to interfere with OC absorption distribution and elimination. Population differences in absorption and elimination have been observed and the clinical implications of these findings on efficacy and side effects requires further investigation. The most rational approach at this time should be based on data generated by clinical trials that rate specific incidences of adverse reactions to specific combination products. The basic pharmacology principle of prescribing the minimally effective dose to achieve the desired effect underlies the recommendation that 1 of the following sub-50mc estrogen combination pills be used initially: Brevicon Loestrin 1.5/30 Lo/Ovral Modicon Norinyl 1+35 Ortho-Novum 1/35 Ovcon-35. The reported incidence of the various symptoms and side effects varies significantly and may be due to populations studied composition and dosage of agents used and differences in study designs.

British Pill Studies Stress Importance of Relation Between Progestogen Content and Vascular Disease

2 major British studies indicate that the progestogen content as well as the estrogen content of combined oral contraceptives probably contributes to increased risk of vascular disease. 1922 cases of suspected cardiovascular reactions to pill use reported to the Committee on Safety of Medicines and accepted for study between 1964 and 1977 were classified as venous or nonvenous and fatal or nonfatal. The researchers obtained pill sales figures for each of the study years to compare observed and expected numbers of reactions to different preparations. Results showed evidence of a statistically significant positive association between progestogen dose and deaths from arterial stroke and ischemic heart disease. A significant positive relationship between dose level and stroke was found in pills containing levonorgestrel. The Royal College of General Practitioners' study was started in 1968 when 23,000 pill users and 23,000 women who had never taken pills were enrolled in the research by their general practitioners. A positive relationship between progestogen dose and hypertension rates was noted between 1975 and 1978. The author of the RCGP report recommends that the progestogen content and the relative potency of the estrogen and progestogen in oral contraceptives be evaluated carefully before prescribing.

Editorial: Outpatient treatment of haemorrhoids.

The estrogenic potency of combined oral contraceptives (OC) is discussed. A dose of 30-50 mcg estrogen was recommended once it was learned that the incidence of thromboembolic disease was related to the estrogen content of OCs. The synthetic progestogens in OCs are usually nortestosterone derivatives, many of which are partly metabolized to estrogen when taken orally. It is difficult, however, to determine whether pills with lowered estrogenicity will reduce the incidence of thromboembolic disorders. Norethynodrel has a purely additive effect on the estrogenicity of estrogens, norgestrel is antagonistic, while norethindrone and ethynodiol diacetate have less estrogenic action at high doses and more action at low doses. It is doubtful that the standard measure for estrogenicity in the mouse uterus is applicable to the association of thromboembolic disease and OC use. The only way to resolve the question is by a more complete epidemiological analysis, which requires greater cooperation in the reporting of thrombotic incidents.

Thin-layer chromatographic identification of estrogens and progestogens in oral contraceptives

A two-dimensional thin-layer chromatographic procedure is described for the separation and identification of the active ingredients of oral contraceptive preparations currently available on the Canadian market. Short-wave ultraviolet light and concentrated sulfuric acid are used for the detection of spots. Observations after spraying with sulfuric acid are tabulated in a color which shows color develoment with respect to time for eleven compounds. The scheme also provides a method for the detection and tentative identification of certain impurities which are frequently found in such formulations.

Importance of the type of the progestogen in oral contraceptives.

Importance of the type of the progestogen in oral contraceptives.