How to choose an oral contraceptive in 1984

The choice of currently available oral contraceptives (OCs) includes combined formulations in varying dosages and monophaic, biphasic, or triphasic form, sequential pills, synthetic progestin-only pills in macro or microdose, and injectable synthetic progestins. Before the advent of microdose pills, products were characterized by progestin or estrogen dominance. Rumors that microdose pills do not completely inhibit ovulation have hindered their acceptance in France, but research has shown that they inhibit ovarian secretions as effectively as more strongly dosed products. Their les profound inhibition of the hypothalamo-pituitary axis raises hopes of a lessened incidence of postpill amenorrhea. Progestin-only microdose pills allow considerable ovarian estrogen secretion, creating a veritable iatrogenic luteal insufficiency. Following the suppression of mestranol, the only estrogen used in OCs is ethinyl estradiol (EE). The only 19-norsteroid progestins which are fixed directly to the progesterone receptors are norethindrone and norgestrel; others such as lynestrenol, ethynodiol diacetate and norethindrone acetate are prohormones. Menstrual problems are among the most frequent side effects of minidose combined pills, but their incidence had dimished with the appearance of biphasic pills and the triphasic pills should offer even greater improvements. The frequency of thromboembolic venous accidents is firectly correlated to the estrogen dose of OCs, but arterial accidents and possibly arterial hypertension appear to be linked to the progestin dose. Synthetic progestins appear to diminish the high density lipoprotein (HDL) fraction of cholesterol and disturb glucose tolerance, while synthetic estrogens augment the HDL fraction of cholesterol and the very low density lipoprotein (VLDL) fraction of triglycerides, modify some coagulation factors, and elevate the plasma level of angiotensinogene. Dose levels and chemical structures of the constituents influence the metabolic effects of pill formulations. In current practice, minidose products are preferred because they cause fewer metabolic changes and are less likely to entail vascular risks. Sequential pills are prescribed for 1 cycle following induced abortion but are not used for long periods because they are not 100% effective, they carry a risk of endometrial hyperplasia, and they appear to increase risks of venous thromboembolism. A combination of 50 mcg EE and 2 mg cyproterone acetate may be prescribed for acne, and minidose combination pills may be used in case of fibroma or endometriosis. In case of contraindications to estrogen, a microdose or injectable progestin can be prescribed if their shortcomings are kept in mind. The current popularity of macrodose progestin-only pills in France has more to do with fashion than with science. All hormonal contraception should be avoided for women at risk, including smokers and those with hyperlipidemia or a family history of vascular accidents.     

Pros and cons of triphasic oral contraception

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.     

Potential advantages of triphasic combined oral contraceptives in the light of recent epidemiological and endocrinometabolic data

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.     

Cardiovascular risks of oral contraceptives: dose-response relationship

This article examines the effect of dose level of both estrogens and progestins as factors in the cardiovascular risk of oral contraceptives (OCs), and also examines the roles of blood pressure, coagulation factors, and lipid metabolism. A large number of epidemiologic studies have demonstrated the connection between OC use and thromboembolic disease since the 1st such study appeared 2 decades ago, but the early studies concerned formulations with much higher estrogen doses than those currently used, taken by women who were older and more likely to smoke than at present. Very few epidemiologic studies dealing with the newer formulations are yet available. It is easier to analyze the dose-response relations for the progestins than for the estrogens given that the 2 estrogens primarily used, ethinyl estradiol (EE) and mestranol, were used for a series of progestins at different doses to examine their effects with a constant dose of estrogen. Nevertheless, the epidemiologic studies show increased risks of thrombotic accidents and a dose-response relation for both the estrogen and progestin components. It is likely that different mechanisms are responsible. The effects of OCs on blood pressure have been monitored carefully since the 1st observations of hypertension in OC users. Blood pressure elevations are usually attributed to the estrogen, but there is evidence of a progestin role as well. Some studies have found differences in blood pressure at the same estrogen dose but with different progestin content. It is very likely that blood pressure undergoes physiologic variations depending on hormonal fluctuations. The mechanism by which some OC users develop hypertension is poorly understood, but it may be related to changes in the renin-angiotensin-aldosterone system. Androgenic progestins accentuate sodium retention, which may play a role. Researchers have shown that the lipid profiles of women at different stages of life are different, whether or not they use OCs. Among young women HDL cholesterol levels decline and LDL levels increase among users relative to nonusers of OCs. On the other hand, old women receiving estrogen substitution therapy tend to have more favorable lipid profiles than do women of the same age not receiving estrogen. Coagulation factors, especially factors VII and fibrinogen, have been established as important cardiovascular risk factors in men. Some studies have shown the levels of factors VII and fibrinogen to be elevated in OC users. These procoagulant alterations are also observed in women receiving estrogen substitution, but unlike OC users such women appear to be protected by age-related increases in the level of antithrombin III. Smoking is an important influence on the fibrinogen level, which probably explains part of the increased risk of myocardial infarct among OC users.     

Rationale for new oral contraceptive dosing

The evolution of both the type and dose of the estrogen and the progestin in oral contraceptives has been complex. Whereas the evolution of the progestin component remains dominated by a concern for the metabolic effects of the 19-nortestosterone derivatives, the evolution of the estrogen component has been more of a concern for safety, or perceived safety. By lowering the estrogen dose, some side effects, such as breast tenderness, bloating and nausea, have decreased. At the same time, others, such as breakthrough bleeding and spotting (BTB/BTS), have increased. Indeed, BTB and BTS are the chief reason why women discontinue OCs as well as the primary reason clinicians change the dose or brand of an OC. During the past few years numerous studies have shown inferior cycle control with 20-microgram ethinyl estradiol (EE) OC formulations compared to slightly higher dose OCs. Recently marketed OCs containing 25-30 micrograms of EE have addressed this issue. The 25-microgram EE OCs combined with desogestrel have cycle control equal to a 35-microgram EE OC, whereas the 25-microgram OC combined with norgestimate has shown superior cycle control compared to a 20-microgram EE OC. The 30-microgram EE OC combined with drospirenone in a non-comparative trial is also associated with low rates of BTB/BTS. Our current goal, now that safety issues have been put to rest, is that of identifying formulations that will enhance adherence and increase successful use of OCs.     

Current developments in hormonal contraception]

The development of hormonal oral contraceptives (OCs) hitherto has been characterized by the endeavor to reduce associated health risks as much as possible without reducing the contraceptive efficacy of menstrual cycle control. This has led to a gradual reduction of the estrogen dose in the OCs as well as to the development of ever more effective gestagens for ovulation inhibition and satisfactory menstrual cycle control. Combination preparations were developed with 30-35 mcg of ethinyl estradiol (EE) and high gestagen doses that guaranteed ovulation inhibition (30 mcg of gestodene, 60 mcg of norgestimate). A three-phase preparation with gestodene, which contains 30 mcg of EE and only 50 mcg of gestodene in the first week, massively suppresses the follicle maturation, more forcefully than an equivalent three-phase OC with levonorgestrel (LNG). In Germany since March 1992, there has been on the market an OC containing 20 mcg of EE and 1 mg of norethindrone acetate, with an effectiveness equal to that of higher-dose OCs. However, with this preparation the rate of spotting was still over 20% in the 12th menstrual cycle of use, hence it has not been accepted. In the coming years it is expected that further combination OCs with 20 mcg of EE and appropriate gestagen components will be introduced. In order to avoid the heavy burden on liver metabolism, various types depot gestagens such as implants (Norplant) or the vaginal ring (180 mcg of estradiol and 290 mcg of LNG) were developed as highly effective alternatives to OCs, however, their menstruation control is not satisfactory. Another implant, Capronor, releases 30-50 mcg of LNG over a period of 12-18 months. Parenterally applied highly effective contraceptive steroids (medroxyprogesterone acetate and norethindrone enanthate injected every 2-3 months) also seem to be able to alter hormone-dependent serum parameters in similar ways as OCs.     

Evaluation of some coagulation tests in women using low dosage oral contraception

This study assessed the effects of 3 types of combined oral contraceptives (OCs) on blood coagulation. The OCs investigated were a monophasic (EE 30 mcg + DOG 150 mcg), another monophasic (EE 30 mcg + LNG 150 mcg), and a triphasic (EE 30 mcg + LNG 50 mcg, EE 40 mcg + LNG 75 mcg, EE 30 mcg + LNG 125 mcg). 60 women between the ages of 19-30 with no contraindications to OC use were randomly recruited and divided into 3 groups. A blood sample was collected at a baseline level, and after 3 and 6 months of use. The parameters examined were antithrombin III, prothrombin time, partial thromboplastin time, fibrinogen degradation products, and protamina sulphate testing. There were no significant changes in any of the coagulation tests during the treatment period with these 3 different OCs. Thus, these OC compounds appear to be equally safe for use. (author's modified)     

Current issues in contraception

Some controversies regarding currently used contraceptive methods are reviewed. There are no newly available estrogens for oral contraceptives (OCs), but 2 progestins are coming into use: cyproterone acetate, which has a potent antiandrogenic action, and desogestrel, which combines a strong inhibitory effect on ovulaion and a marked peripheral progestin activity with very weak androgenic and anabolizing activity. New systems of administration will be used in the future to avoid the serum "peaks" observed in oral administration. The lack of agreement on the effects and secondary effects of various progestins will be a continuing source of discussion. 2 aspects of combined OCS, residual ovarian activity and androgenicity, are attracting increasing attention. Among new preparations, the combination of 2 mg cyproterone acetate and 50 mcg of ethinyl estradiol (EE) has been shown in multicenter European studies to have good effects on acne and satisfactory acceptance despite some hyperestrogenic secondary effects, which may be improved by a new dosage schedule. Triphasic preparations have given good results with significantly reduced steroid doses. There have been few recent findings concerning risks of OCs. The triphasic formulations and those containing desogestrel are too recent to have been subjected to epidemiologic study. The noncontraceptive benefits of OCs are becoming more apparent; they include protection against ovarian and endometrial cancer, functional ovarian cyst, ectopic pregnancy, salpingitis, benign breast disease, dysmenorrhea, rheumatoid arthritis, menorrhagia, and premenstrual syndrome. Improved knowledge of the mechanisms of action and local effects of IUDs permitted improved utilization. Ultastructural studies and endometrial exploration have show that non-fundally located IUDs entail greater risk of failure and complications. The question of early pregnancy with IUD use is still unresolved. Copper IUDs are now the most widely used type, but there are differences of apinion about whether the copper content should be increased or whether silver should be added to the core of the copper thread. IUDs with natural or synthetic progesterone may reduce bleeding and have other beneficial effects. Currently it is impossible to identify 1 particualr IUD as superior. IUD performance is improved by careful patient selection, choice of IUDs, and follow-up to identify and treat problems at an early stage. Improved spermicides such as Benzalkonjum chloride attracted greater attention to vaginal methods. The posibility of increased risk of toxic shock syndrome and teratogenic effects remain to be evaluated. Post-coital contraception continues to be important as yet no satisfactory new male methods have been developed. The US office of Technology Assessment has published a list of contraceptive developments or improvements expected by the year 2000.     

Individualization of low-dose oral contraceptives. Pharmacological principles and practical indications for oral contraceptives

The contraceptive pill has been a revolution of the last 40 years. In Italy, however, it is much less widely used than in other countries. Explanations for this phenomenon range from religious implications and customs to misinformation and word-of-mouth communication of negative experiences. The oral contraceptive pill is often used to correct menstrual disorders, leading to poor results and side-effects. Recent advances in oral contraception have led to a substantial reduction in doses and side-effects. Low-dose pills contain minimal doses of progesterones and estrogens and ensure good control of the menstrual cycle. Although reduction of ethinyl estradiol (EE) concentrations has reduced the incidence of negative systemic side effects such as water retention, edema and swollen breasts, the low estrogen dose may be associated with spotting and hypomenorrhea or amenorrhea in the long term, as well as dyspareunia due to reduced vaginal trophism, which may induce women to suspend use of the drug. It is also true that only one type of estrogen is used in the pill, albeit at different doses, whereas the progesterone may differ and in many cases is the cause of common side-effects. The choice of progesterone therefore involves not only its effect on the endometrium in synergy with estrogen, but also possible residual androgenic activity which may have negative metabolic repercussions. Indeed, addition of a progesterone, especially androgen-derived, attenuates the positive metabolic effects of estrogen. Two new monophasic oral contraceptives were recently released. They contain 30 microg (Yasmin) or 20 muicrog (Yasminelle) EE and a new progesterone, drospirenone, derived from spirolactone, which has antiandrogenic and antimineralcorticoid activity similar to endogenous progesterone. Like progesterone, the drospirenone molecule is an aldosterone antagonist and has a natriuretic effect that opposes the sodium retention effect of EE. It may, therefore, help to prevent the water retention, weight gain and arterial hypertension often associated with oral contraceptive use. Recent comparative studies recorded weight loss that stabilized after 6 months of treatment with drospirenone/EE. Overweight women may therefore benefit from the formulation with 20 microg EE, whereas the formulation with at least 30 microg EE should be more appropriate for underweight women. Women with slight to moderate acne, the formulation with 30 microg EE has been found to be as effective as 2 mg cyproterone acetate combined with 35 micrig EE (Diane). Menstrual cycle characteristics, however, remain the main factor determining the choice of formulation. Randomised control studies comparing the new formulation with others containing second or third generation progesterones have found similar efficacy in cycle control and incidence of spotting. From this point of view, it is not advisable to prescribe more than 30 microg EE (Yasmin or Yasminelle) for women with normal menstrual cycles, whereas in cases of hypomenorrhea and/or amenorrhea at least this dose of EE plus drospirenone may be used. Women with hypermenorrhea run the risk of spotting if an inappropriate drug is chosen. A solution is to use 30 microg EE/drospirenone from day 5 of the cycle. To control so-called minor side-effects, the dose of EE must be appropriate. In women with premenstrual tension a dose of at least 30 microg EE associated with drospirenone reduces or even prevents symptoms. On the other hand, in cases of chronic headache or headache as a side-effect of oral contraceptive use, a lower dose of estrogen is beneficial, and doses below 20 microg may be used. Although the progesterone component is not considered to affect headache, good results have been obtained with drospirenone, the antimineralcorticoid effects of which reduce blood pressure and improve symptoms. Formulations with 20 microg EE and drospirenone are particularly indicated in women with pre-existing mastodynia, fibrocystic breast manifestations or who develop mastodynia as a side-effect of oral contraceptive use. Since high plasma concentrations of androgens have been recorded in these women, a progesterone with antiandrogen and antiedema activity can be beneficial. Finally, it is worth recalling that monophasic pills with low estrogen doses, such as the formulations mentioned above, ensure good mood control, reducing the depressive symptoms often associated with oral contraceptive use. In conclusion, formulations containing drospirenone are a valid alternative to conventional oral contraceptives for the personalisation of these drugs.     

Combination oral contraceptive pills: How do they differ?

Combination oral contraceptive pills (OCPs) are the most common method of reversible contraception. All low-dose OCPs contain the same estrogen component, ethinyl estradiol, usually 30–35 μg. The principal variable in low-dose OCPs is the progestin component. Progestins can be divided into three major categories: levonorgestrel, norethindrone, and the new progestins. These progestins differ in their androgenicity, allowing the health care provider to select OCPs depending on the individual patient's characteristics and symptoms. Oral contraceptive pills containing 50 μg of ethinyl estradiol have limited but definite indications including use in patients on antiepileptic drugs, recurrent ovarian cyst formation, and persistent breakthrough bleeding on low-dose OCPs. Triphasic formulations do not appear to offer major advantages over monophasic OCPs. Unfortunately, accurate OCP knowledge by the general public is lacking, with many women believing that the pill causes serious health problems. In addition, most women are unaware of many of the major noncontraceptive benefits including cancer protection. Oral contraceptive counseling including dispelling the myths, detailing the noncontraceptive benefits, and reviewing potential side effects is mandatory to enhance compliance.     

The emerging use of the 20-microg oral contraceptive

OBJECTIVE: To highlight studies that investigated the efficacy, safety, and tolerability of low-dose oral contraceptives (OCs) containing 20 microg of ethinyl estradiol (EE) and to discuss the use of these low-dose contraceptives in women from adolescence to menopause and the noncontraceptive health benefits likely to be afforded by low-dose contraceptives. DESIGN: Relevant literature was identified by searching MEDLINE and EMBASE. Other sources were located by consulting the bibliographies of the material collected from Medline and EMBASE. Sources for additional information included documents from the United States Food and Drug Administration and the Physicians' Desk Reference (54th ed.). CONCLUSION(S): The current lowest available dose of EE used for OCs in the United States is 20 microg. Formulations with 20 microg of EE are efficacious and have a low incidence of estrogen-related side effects. Since this lowest effective EE dose inhibits ovarian activity, 20 microg of EE should also provide the noncontraceptive health benefits of OCs. Both contraceptive and noncontraceptive benefits of OCs are available to most women from adolescence to menopause without complications.     

The antinidatory activity of oral contraceptives

This work examines the importance of the antinidatory effect of combined and low-dose progestin oral contraceptives (OCs). The greater importance of inhibition of ovulation and coagulation of the cervical mucus as mechanisms of action of OCs has caused the role played by transformations of the endometrium to be neglected. But the hormone-induced inhospitability of the endometrium to implantation of the accidentally fertilized embryo should be assessed because of the occasional occurrence of pregnancies in women using pills and because inhibition of ovulation is never complete, especially in the case of low-dose progestins which only prevent ovulation half the time. Ovulation inhibition is very powerful in principle when no pills are forgotten. Some research using the techniques of "programmed forgetting" has indicated that inhibition is not complete in all users, especially when one or more pills are skipped. Elevated serum concentrations of estradiol, the pituitary gonadotropins, and progesterone have been reported. Research suggests that the cervical mucus and endometrial effects are not significantly influenced by pill forgetting. The Pearl indexes of different OC formulations attest to the occurrence of pregnancy in women using pills. Most reported Pearl indexes are corrected to account for pill forgetting. Some surveys suggest that forgetting pills is not rare, and it may be argued that uncorrected Pearl indexes would be a more reliable reflection of actual conditions of use. The uncorrected Pearl index might be one or two pregnancies per 100 woman-years during standard use including inevitably some forgetting. In the absence of easily used markers to detect the presence of an embryo before implantation, the antinidatory effect of endometrial atrophy cannot be directly demonstrated. It may be hypothesized that the antinidatory effect is a kind of resistance of the endometrium to implantation. In other words, a much smaller proportion of embryos conceived under OCs would successfully be able to implant than would be true under conditions of no OC use. The "index of embryonic destruction" based on current knowledge of uncorrected Pearl indexes, can be estimated at 3 to 10 embryos destroyed for one or two pregnancies per 100 woman-years of use of combined OCs and 6 to 30 per 100 woman-years of use of low-dose progestins.     

Low-dose contraceptive estrogen-progestin and coronary artery atherosclerosis of monkeys

OBJECTIVE: To determine the separate and combined effects of the estrogen and progestin components of a modern triphasic oral contraceptive (OC) formulation on extent of coronary artery atherosclerosis. METHODS: Female cynomolgus monkeys (n = 81) were fed atherogenic diets for 32 months. After the first 7 months, they were randomized to four groups and treated triphasically for 21 of each 28 days with ethinyl estradiol (E2) (monkey equivalent of 30-40 microg), levonorgestrel (monkey equivalent of 50-125 microg), a combination of the two steroids, or placebo. RESULTS: Treatment with estrogen alone reduced coronary artery atherosclerosis extent 67% compared with untreated controls (P <.05). Treatment with progestin alone had no effect (P >.20). While atherosclerosis extent in monkeys treated with the combined OC was reduced 28%, this did not differ statistically from the other groups (P >.20). CONCLUSION: In doses used for oral contraception, E2, like all other estrogens studied to date, has a marked inhibitory effect on atherosclerosis progression. Levonorgestrel, at doses used in modern OC formulations, antagonizes this effect. When considered with other experimental evidence, these findings support the concept that progestins used in OCs and hormone replacement therapy can antagonize estrogen's atheroinhibitory effects. Whether this occurs seems to depend on a relative balance between estrogen and progestin with respect to dose, potency, route, and pattern of administration. However, when considered with evidence from previous studies, the findings also indicate a modest atheroinhibitory influence of combination (estrogen-progestin) OCs.     

Benefits and risks of hormonal contraception]

In addition to oral contraceptives (OCs), the morning-after pill, the minipill, and depot preparations also belong to hormonal contraceptives. The latter two contraceptives have not become established among young women because of inadequate cycle control. For postcoital contraception in Austria, Neogynon and Stediril-D, consisting of 0.05 mg of ethinyl estradiol (EE) + 0.25 mg of levonorgestrel, are used within 48 hours of unprotected intercourse. Lower dose OCs have considerably reduced the risks of side effects. Micropills are the optimal OCs with EE under 50 mcg combined with the new generation of gestagens. The beneficial effects include menstrual regularity and the prevention of anemia, ovarian cysts, and fibrocystic mastopathy. Nausea, headache, spotting, and weight gain do occur in individual cases, even among young people. The potential risk of thromboembolism is the most important, although arterial cardiovascular risk is minimal in young age. The probability of postpill amenorrhea is less than 1%. Micropills can be used by young diabetics provided the disease is not beyond 10 years' duration and there is no angiopathy. Acne, seborrhea, and hirsutism are beneficially influenced by a combination of 0.035 mg of EE with 2 mg of cyproterone acetate. The relative risk of endometrial and ovarian cancer are only about half as high among OC users as among nonusers. The risk of breast cancer in young OC users has not been conclusively explained. Regular colposcopy and cytology is recommended for young OC users to preclude the risk of malignancies of the genital tract. Sex education and the use of OCs that are the most suitable and effective for young people can reduce the number of unwanted pregnancies and abortion. The comparison of two 5-year periods in the 1970s and 1980s at the University Obstetrical-Gynecological Clinic in Graz showed that the incidence of births among women under 18 years of age decreased from 3.6% (778) to 1.6% (353).     

The progestogen-only pill

This commentary reviews the indications for and side effects of the progestogen-only oral contraceptive (OC) pill, which accounts for under 3% of hormonal contraceptive sales in the UK. The progestogen-only pill has the advantage of fewer metabolic changes, a lower dose of progestogen, and avoidance of the use of estrogen. It is the hormonal method of choice for breast feeding women, older women, and women who are unable to tolerate an estrogen-containing preparation. Its failure rate ranges from 0.9 to 3.0/100 woman-years, which is comparable to that for other reversible methods. The failure rate tends to be lower in older age groups, perhaps reflecting advancing sensitivity with age to the contraceptive effects of progestogen. The major problem associated with use of progestogen-only contraceptives is irregular vaginal bleeding, experienced by 20-30% of users. Progestogen has been reported to induce a variety of effects on the endometrium as well as in ovarian steroid secretion. A high prevalence of functional ovarian cysts has been noted in users. It is now believed that the contraceptive efficacy of the progestogen-only pill depends more upon its effects on ovarian function than was previously realized. A new approach to overcoming some of the problems associated with progestogen-only contraception has involved combining progestogen with sulpiride. This combination appears to be more effective than either component alone in suppressing ovarian activity. There is a need to make progestogen-only OCs more widely available to women in developing countries, where 30-40% of women of reproductive age may be breast feeding at a given time. Numerous studies have demonstrated either no effect or a beneficial effect on lactation.     

Contraception for the diabetic woman

Because of their vascular and metabolic risks for diabetic women, pregnancies must be carefully programmed to occur before the onset of degenerative diabetic manifestations. Diabetic women need an effective contraceptive method without undesirable side effects. The numerous side effects of combined oral contraceptives (OCs) are due to both the estrogens and progestins. Combined OCs have a diabetogenic effect whose mechanism is not clearly understood. Blood sugar levels are elevated under OCs and the insulin response is retarded and exaggerated. The number and affinity of insulin receptors are reduced. Norsteroid- derived progestins increase the state of insulin resistance. Combined OCs usually increase triglyceride levels. Changes in the level of high- density lipoprotein cholesterol under combined OCs vary with the estrogen and progestin content. Synthetic estrogens increase platelet aggregability, and blood pressure increases during OC use. Use of combined OCs represents increased vascular risk for diabetic women, with the risk of thrombosis multiplied by 4. Low dose progestin pills permit continued secretion of a small amount of luteinizing hormone and follicle stimulating hormone which may cause a relative hyperestrogenism and undesirable side effects. The secondary effects are often poorly tolerated. Use of this type of pill is limited except among diabetic women, 25% of whom are users. The failure rate is estimated at .2-2%. Standard-dosed norsteroids are unsuitable for diabetic women because of their metabolic and vascular side effects. 2nd and 3rd generation progestins have yielded more promising results. IUDs are used by about 12% of the overall female population but 32% of diabetic women, mostly multiparas, despite the increased risk of infection. Local methods have a higher failure rate and their success depends on patient compliance with instructions. 14% of diabetic women in a recent survey reported having undergone tubal ligation, which is not strictly speaking a contraceptive method. Combined OCs should be avoided in insulin- dependent diabetics because of their metabolic and vascular effects. Diabetic retinopathy should be added to the list of absolute contraindications to these methods. Low-dose progestins can be used in insulin-dependent diabetics or if they are poorly tolerated a standard dose pill can be substituted. IUD is the method of choice for older, multiparous insulin-dependent diabetics. Sterilization may be considered, especially if pregnancy is absolutely contraindicated. Combined OCs are formally contraindicated for noninsulin-dependent diabetics. Low-dose progestins could be tried. IUDs are suitable for multiparas.     

Do's and don'ts in post-partum contraception

It is sometimes difficult to plan contraception with a woman who has just delivered a baby, because she is sometime not motivated in the week following delivery, feeling unable to contemplate intercourse because of perineal pain and other discomforts. Effective contraception should be used beginning with the 25th postpartum day because of the subsequent strong possibility of ovulation before the return of menstruation. The woman should be provided with as much information on contraception as possible during this period, and possible contraindications to specific methods should be sought, such as thromboembolic accidents, hyperlipidemia, hypertension, diabetes, infection, ectopic pregnancy, abortion, and desire for subsequent pregnancy. No request for contraception should be ignored and the same method should not be imposed on all women. The topic of contraception should not be deferred until the postpartum check-up in the 2nd month, because 50% of women will have had intercourse by the end of the 2nd month, often unprotected. Local methods such as spermicides and condoms are effective when the couple is motivated and they are well accepted. The thromboembolic risk appears minimal when oral contraceptives (OCs) are begun on the 15th postpartum day for non-breastfeeding women. OCs should not be prescribed for women after prolonged bedrest, and women who previously used pills should have lipid and glucose tests before the 2nd month postpartum consultation. The low dose progestin pill should be preferred to the low dose combined pill if a potential thromboembolic risk exists. Infants of breastfeeding women using pills receive 1/500 of the estrogen dose administered to the mother and 1/1000 of the progestin dose. No effects of these doses have been found on the growth or genital development of infants, and modifications of milk composition are not constant. A low dose progestin pill beginning on postpartum day 20 may however be preferred. It is better to await the return of menses before inserting an IUD because of the danger of expulsion prior to that time. Local methods should not be the only ones recommended in the immediate postpartum period because of the possibility of poor acceptance and unwanted pregnancy resulting from incorrect use. Very high dose OCs should not be prescribed. Long acting injectable progestins should be avoided for breastfeeding women except in cases of serious psychic disturbance because the quantity of hormones entering the milk is much greater than with pills.     

Current status of contraceptive vaginal rings

Vaginal administration of contraceptive steroids has several advantages over oral administration, including avoidance of the digestive tract and the 1st passage effect, continuous release of the active principle allowing lower doses and fewer side effects, independence of the method from sexual relations, and possibility of application directly by the user. An early vaginal ring containing medroxyprogesterone acetate in silastic inhibited ovulation but released the progesterone in large initial bursts followed by rapid decline, offering no advantage over parenteral administration. The problem was resolved through development of a vaginal ring with an inert core covered with a fine layer of a mixture of silastic and progesterone, in turn covered by a fine layer of silastic. The speed of release of the new ring was proportional to t he surface of the ring and inversely proportional to the thickness of the outer layer. This method was used to release variable quantities of levonorgestrel over 3-6 cycles, which inhibited ovulation in 85% of users but provided only mediocre cycle control. The World Health Organization at about the same time was sponsoring research focussed on development of a vaginal ring releasing small doses of progestins with a minimal blocking of ovulation but a major contraceptive effect at the level of the cervical mucus and endometrium. Several progestins were evaluated and dose-response tests were conducted on a number of them. A ring releasing 20 mcg/day of levonorgestrel was found to cause fewer cycle problems and to have a moderate affect on ovarian function. The Population Council in New York developed a method adding estrogen to the progestin to resolve the problem of irregular bleeding and obtain better cycle control. Development was halted despite promising results because of difficulties of mass production and the results of metabolic studies that indicated the method had undesirable effects on lipoprotein levels. But large scale multicountry trails with the levonorgestrel-releasing ring continued to give positive results. Bleeding problems, when they arose, were less serious than those with low-dose oral progestins. The efficacy was at least equal. A detailed study of social acceptability found the level of acceptability of the vaginal ring to be high, with women appreciating their ability to remove the ring themselves. Despite the favorable results, marketing of the levonorgestrel vaginal ring was delayed by problems in mass production and in procuring adequate supplies of silastic. Recent developments have included new lightweight plastics and a model that allows the ring to be divided into sections. A multicenter study is underway of a ring releasing 120 mcg of desogestrel and 30 mcg of ethinyl estradiol. Results have been very favorable. A vaginal ring is likely to be commercially available by 1995.     

三种低剂量、复方口服避孕药的临床比较性研究

本文应用随机化双盲法,对三种低剂量含雌、孕甾体激素避孕药(含18-甲基炔诺酮及炔雌醇的复方三相制剂,含18-甲基炔诺酮150μg及炔雌醇30μg的固定剂量制剂,含炔诺酮600μg及炔雌醇35μg的Ⅰ号避孕药)进行比较性研究。共收集合格健康育龄妇女279例;其中复方三相制剂96例,固定剂量制剂93例,Ⅰ号避孕药90例。按生命表法统计,其6个月的每百妇女累积续用率:复方三相制剂82.3,左旋18-甲基炔诺酮/炔雌醇固定剂量制剂81.6,Ⅰ号避孕药80.9,三组间在统计学上无显著差别。副反应的发生率,三组间亦甚相似。有关出血类型:在复方三相制刺中月经周期较为规则,滴血最为少见,行经期长度亦较少受影响。研究证实复方三相制剂是一种有效的低剂量口服避孕药,值得进一步研究。