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PIP: A German court recently ruled in favor of a contraceptive manufacturer by lifting the ban against prescribing oral contraceptives (OCs) containing gestodene or desogestrel (so-called "third generation OCs") to first-time users under age 30. This ban had been imposed by the health regulatory agency, the defendants in the lawsuit. This ban was issued in response to a controversy initiated in 1995 when the British Committee on the Safety of Medicines cited an increased risk of venous thromboembolism with use of these OCs. In the US, no OCs are available containing gestodene, and only two formulations contain desogestrel. While the US Food and Drug Administration stated that the increased risk was not sufficient to warrant switching patients from third-generation OCs, many clinicians refrained from prescribing the drugs, especially to first-time users. Some US clinicians see the German Court's ruling as vindication for their continued support for the product and report fewer side effects and better lipid-neutral profiles in users of these OCs. A proportion of women will develop deep vein thrombosis upon initiation of OC use, and these women stop using OCs. The newer formulations may appear riskier because they attract more new users, but a recent reexamination of the data from one of the original studies that led to the ban indicates that second- and third-generation OCs are associated with an identical risk of venous thromboembolism.^ieng

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OBJECTIVES: The aim of this study was to assess preferential prescribing of OC according to different thrombotic risk factors. MATERIAL AND METHODS: The control group in an ongoing Danish case-control study on stroke and OCs collected in 1994 and 1995 underwent a control-only analysis concerning the occurrence of thrombotic risk factors among users of different types of OC. Specific attention was given to differences between OCs with second and third generation progestagens. The association between specific risk factors and the pill types was assessed crude and after multivariate analysis with confounder control for age and other risk factors, in order to identify risk factors, which after these corrections still had a significant confounding influence on the prescribing of OC. RESULTS: Users of OCs with third generation progestagens had a significantly higher proportion of familial thrombotic disposition (23.1%) than users of OCs with second generation progestagens (7.1%) (p = 0.01). After correction for age and other risk factors this difference was still highly significant (p = 0.002). Among users of third generation pills the proportion of short time users (< 1 year) (22.4%) was significantly higher than the per cent among users of OCs with second generation progestagens (5.5%) (p < 0.001). This difference was still significant after correction for age and other risk factors (p < 0.001). Smoking, years of schooling, migraine, and body mass index did not differ significantly between the two pill groups. CONCLUSION: In Denmark, women with familial thrombotic disposition are four times more likely being prescribed OCs with third versus second generation progestagens compared with women without such a disposition. At the same time users of OCs with third generation progestagens include significantly more short time users than users of OCs with second generation progestagens. For thrombotic diseases where familial disposition or duration of use of OCs play a role for the pill-associated risk, these differences may significantly influence the thrombotic risk measures in case-control studies and non-randomized cohort studies unless confounder control is conducted for this selection.

PIP: An analysis of the occurrence of thrombotic risk factors among users of different types of combined oral contraceptives (OCs) revealed the existence of differential prescribing patterns based on these risk factors. The 206 study participants were among the 1200 controls in a 1994-95 Danish case-control study on stroke and OCs. The 118 users of third-generation OCs containing the progestins desogestrel or gestodene had a significantly higher rate of familial thrombotic disposition (23.1%) than the 56 users of second-generation OCs containing levonorgestrel, norgestrel, and norgestimate (7.1%). Even after adjustment for age and other risk factors, this trend remained significant (p = 0.002). This finding suggests that general practitioners are asking women about thrombotic familial disposition before prescribing OCs and basing the OC type on this information. In addition, there were significantly more short-time users (under 1 year) among users of third-generation OCs (22.4%) than of second-generation OCs (5.5%). This difference also remained significant after adjustment for age and other risk factors (p 0.001). There were no differences between the OC groups in terms of smoking, educational attainment, migraine, and body mass index. Since both thrombotic disposition and duration of OC use may influence the risk of thrombotic diseases, these potential confounders should be controlled in epidemiologic analyses of OC-related thromboembolic risks.

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PIP: In July 1996, seven months after the publication of evidence linking third-generation oral contraceptives (OCs) to an increased risk of venous thromboembolism, the New Zealand Ministry of Health issued guidelines for physicians on this topic. Although all combined OCs increase the odds of thromboembolic events, preparations containing desogestrel or gestodene are associated with a two-fold greater risk than first- or second-generation OCs. In 1995, the UK Committee on the Safety of Medicines advised physicians not to prescribe OCs containing desogestrel or gestodene to women with risk factors for venous thromboembolism and recommended that current users should continue with these preparations only if they could not tolerate other OCs. The New Zealand recommendations are less directive. Doctors are advised that, when initiating OC therapy, they should consider prescribing OCs containing no more than 35 mcg of ethinyl estradiol and a progestogen other than desogestrel or gestodene; it is noted, however, that third-generation OCs may have an additional therapeutic role in specific medical conditions. In New Zealand, about 75% of OC users (compared to 50% in the UK) use these new OCs and about 40 of the 50 expected cases of venous thromboembolism in New Zealand pill users per year will occur in women taking OCs containing desogestrel or gestodene.^ieng

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PIP: Recent studies suggesting that oral contraceptives (OCs) containing the progestins desogestrel and gestodene are associated with a two-fold increased risk of nonfatal venous thromboembolism (VTE) compared to earlier formulations have raised new issues for clinicians. The increased risk of 20-30 cases of VTE per 100,000 women annually compares with 60 VTE cases associated with pregnancy. Women with a documented history of unexplained VTE should not use OCs, and when there is a family history, physicians should weigh factors such as age of onset of thrombosis in the affected relative, the clinical setting (e.g., after surgery or trauma), and severity of the episode. The effects of OCs on procoagulants and anticoagulants are minor, except in the 5% of women with factor V Leiden mutation. A clotting assay can determine activated protein C resistance and a polymerase chain reaction test can identify the presence of this mutation; however, widespread screening of OC users is not recommended due to the low incidence of factor V Leiden and the low likelihood these women will develop clots. The present state of knowledge about OCs and VTE risk supports the application of informed clinical judgment.^ieng

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PIP: A review of recent epidemiologic studies that have detected an association between the use of oral contraceptives (OCs) containing the progestins gestodene and desogestrel and venous thromboembolism (VTE) risk suggests evidence of bias. Reviewed are five major case-control and cohort studies: World Health Organization Collaborative Study, Boston Collaborative Drug Surveillance Program Study, European Transnational Study, and the Leiden Study. Three major sources of bias could account for the increased VTE risk among users of third-generation compared to second-generation OCs: 1) selective prescription of newer formulations to higher-risk women; 2) the increased tendency for women with suspected VTE to be more likely to be referred for diagnostic testing and hospitalization if they are taking the newer OCs rather than older formulations; and 3) attrition of susceptibles. The lack of any proposed biological basis for the observed association between VTE and the new progestins, compared with previous knowledge about the responsibility of estrogen for increased VTE risk, raises additional doubts about the findings. Any evaluation should balance the effects of OCs on overall risk of cardiovascular disease against protection from pregnancy and noncontraceptive health benefits such as a reduced risk of certain cancers.^ieng

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PIP: Compared to the risks inherent in pregnancy and daily activities of living, the increased risk of nonfatal venous thromboembolism (VTE) among users of oral contraceptives (OCs) containing desogestrel and gestodene is relatively benign. About 20-30 cases of nonfatal VTE per 100,000 users of third-generation OCs containing these progestins can be expected compared to 10-15 cases per 100,000 users of levonorgestrel-containing OCs. Pregnancy, on the other hand, confers an increased risk of about 60 cases of nonfatal VTE per 100,000 women. Since OCs remain the most popular reversible method of birth control, their discontinuation because of VTE concerns would have serious public health consequences in terms of unwanted pregnancy prevention. Moreover, OCs confer a number of noncontraceptive health benefits, including protection against ovarian and endometrial cancer, osteoporosis, benign breast disease, ovarian cysts, and pelvic inflammatory disease. The lives saved by OCs should be considered in any analysis of the small VTE risk they may impart.^ieng

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PIP: Information on the association between combined oral contraceptives (OCs) and cardiovascular disease risks has been derived almost exclusively from studies in developed countries. To assess this relationship in developing countries, where the risk factors for cardiovascular disease may be different, a case-control study of venous thromboembolism, stroke, and myocardial infarction was carried out in 21 centers in 17 countries in Africa, Asia, Europe, and Latin America. The World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception enrolled 3800 cases of stroke, venous thromboembolism, and myocardial infarction and 11,200 matched controls. Studies in the UK had suggested that OCs containing desogestrel and gestodene doubled the risk of venous thromboembolism compared with levonorgestrel and norethindrone-containing OCs. The multi-center study identified an overall risk of venous thromboembolism in the lower range of that reported in developed countries, an increased risk soon after starting OC use but elimination of such risk within a few months after pill discontinuation, and slightly increased risk among obese women and those with a history of high blood pressure during pregnancy. Unexpected was the finding that women who use OCs containing desogestrel or gestodene may be at double the risk of blood clotting in the veins compared with users of OCs containing levonorgestrel or norethindrone. Although these findings remain controversial, several countries have modified OC prescribing practices to eliminate women at high risk of cardiovascular disease.^ieng

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As GSD is the most potent progestogen used in oral contraceptives, the doses of GSD can be lower than those of other progestogen components. The monophasic (30 micrograms EE + 75 micrograms GSD) and the triphasic formulation (30 micrograms EE + 50 micrograms GSD/40 micrograms EE + 70 micrograms GSD/30 micrograms EE + 100 micrograms GSD) suppress gonadotropin release and ovarian function profoundly and inhibit ovulation reliably. The strong anti-estrogenic and progestogenic effectiveness of GSD is based on the high GSD serum concentrations achieved during daily intake. Because of the weak androgenic properties of GSD, both formulations can be characterized as estrogen-dominant with respect to their hepatic effects. Except for the first cycles, both formulations afford good cycle control, and the rate of side effects is similar to that with comparable low-dose oral contraceptives. The levels of total and free androgens and androgen precursors, as well as of peripheral androgen activity, are significantly reduced, resulting in a reduced incidence of acne. The concentrations of SHBG and other serum-binding globulins are elevated considerably, and thyroid function is almost unaffected. The estrogen-dominant effect on hepatic metabolism of both formulations also is reflected by a significant increase in the levels of triglycerides and VLDL, HDL, and some apolipoproteins, while LDL-CH and total CH remain unchanged. Similar to other low-dose oral contraceptives, the GSD-containing preparations cause a slight impairment of glucose tolerance that does not appear to be of clinical relevance. However, a significant increase exists in pro-coagulatory and fibrinolytic activity that leads to a considerable stimulation of fibrin turnover. In predisposed women, this may contribute to an elevated risk of venous and arterial thromboembolic diseases.

PIP: Gestodene (GSD) is the most potent and therefore lowest dosed progestogen used in oral contraceptives. Pharmacokinetic studies have found serum levels of GSD to be considerably higher than those of comparable progestogens taken at higher doses. The monophasic and triphasic formulation suppress gonadotropin release and ovarian function profoundly and inhibit ovulation reliably, with GSD's strong anti-estrogenic and progestogenic effectiveness based upon the high GSD serum concentrations achieved during daily intake. The authors describe the pharmacologic properties of GSD, formulations containing GSD and ethinyl estradiol, pharmacokinetics, contraceptive effectiveness, cycle control and side effects, the effect on hormonal parameters, the effect on lipid metabolism, the effect on carbohydrate metabolism, and the effect on hemostasis.

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OBJECTIVE: To review and compare the newer progestins desogestrel, norgestimate, and gestodene with regard to chemistry, pharmacokinetics, efficacy, and tolerability. DATA SOURCES: Primary literature on desogestrel, norgestimate, and gestodene was identified from a comprehensive MEDLINE English-literature search from 1984 through 1994, with additional studies selected by review of the references. Indexing terms included progestins, desogestrel, gestodene, norgestimate, levonorgestrel, and norgestrel. STUDY SELECTION: Only human clinical and pharmacokinetic trials performed in Europe, Canada, and the US were included. DATA EXTRACTION: All available data from human studies were reviewed; both comparative and noncomparative studies were included because of the paucity of direct comparative information available. DATA SYNTHESIS: The newer progestins were designed to minimize the adverse effects (e.g., acne, hirsuitism, nausea, carbohydrate and lipid metabolism changes) observed with older oral contraceptives (OCs) while maintaining efficacy and good menstrual cycle control. Desogestrel, norgestimate, and gestodene have minimal amounts of androgenicity and antiestrogenic potential. All of these agents are pharmacokinetically similar to older agents: they are highly bioavailable when administered orally, hepatically metabolized, and obtain steady-state concentrations after 8-10 days of continuous administration. The newer agents have similar Pearl Indexes and slightly better cycle control. Furthermore, the new progestins appear to cause fewer adverse effects, such as acne and hirsuitism, and similar rates of weight gain, blood pressure changes, and lipid and carbohydrate metabolism changes. CONCLUSIONS: Desogestrel, norgestimate, and gestodene appear to offer clinical advantages because of their decreased androgenicity. Women whose cycles are currently well controlled with other OCs should not be switched to a newer progestin. However, any of the combination OC products that contain these progestins may be prescribed for women intolerant of older agents or to first-time users of OCs. The newer progestins appear to be efficacious and offer similar cycle control, improved safety and tolerability profiles, and comparable price with the older agents.

PIP: The objective was to review and compare the chemistry, pharmacokinetics, efficacy, and tolerability of the newer progestins desogestrel, norgestimate, and gestodene. Data sources were primary literature on desogestrel, norgestimate, and gestodene identified from a comprehensive MEDLINE English-literature search from 1984 through 1994, with additional studies selected by review of the references. Only human clinical and pharmacokinetic trials performed in Europe, Canada, and the US were included. All available data from human studies were reviewed; both comparative and noncomparative studies were included. The newer progestins were designed to minimize the adverse effects (e.g., acne, hirsutism, nausea, blood pressure elevation, carbohydrate and lipid metabolism changes, hemostatic changes) observed with older oral contraceptives (OCs) while maintaining efficacy and good menstrual cycle control. Desogestrel, norgestimate, and gestodene have minimal amounts of androgenicity and antiestrogenic potential. All of these agents are highly bioavailable when administered orally, hepatically metabolized, and obtain steady-state concentrations after 8-10 days of continuous administration. These agents have similar Pearl Indexes and slightly better cycle control than older agents. They appear to cause fewer adverse effects such as acne and hirsutism, and similar rates of weight gain, blood pressure changes, and lipid and carbohydrate metabolism changes. Desogestrel, norgestimate, and gestodene appear to offer clinical advantages because of their decreased androgenicity; however, available data are based on relatively small studies of short duration. Women whose cycles are currently well controlled with other OCs should not be switched to a newer progestin. However, any of the combination OC products that contain these progestins may be prescribed for women intolerant of older agents or to first-time users of OCs because of their apparent efficacy, improved cycle control, superior safety, tolerability, and comparable prices. Patients who have significant acne or hirsutism with older products and diabetic women may experience clinically significant benefit with the newer agents.

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Clinical results of a new contraceptive pills--Marvelon (Organon) were studied. 32 women, ages 30 +/- 5 years, participated in the study during at least 6 cycles. Marvelon was good tolerated and subjective side-effects were very low. The cycles were regular, duration of withdrawal bleeding was 3-5 days and the amount of the blood lost were unchanged or milder. Marvelon didn't affect body weight and blood pressure. Favourable lipid profile--increased a mean level of HDL-Cholesterol and decreased a mean level of LDL-Cholesterol were noticed. Pearl Index was 0,0.

PIP: Marvelon is an oral contraceptive of the third generation of contraceptives introduced in the 1980s. These preparations contain progestagens (desogestrel, gestodene, and norgestimate) and ethinyl estradiol. Marvelon contains .03 mg of ethinyl estradiol and .15 mg of desogestrel. The results of clinical use of Marvelon (made by Organon), were studied in 32 women aged 30 +or- 5 years in the course of at least six cycles. Marvelon was well tolerated and the subjective side effects were minor. The cycles were regular and withdrawal bleeding lasted 3-5 days. The duration of menstrual cycles with the use of Marvelon constituted 27-30 days. The amount of bleeding did not change in 26 women, while it became less in 6 women. Marvelon did not affect body weight and blood pressure. The weight of the patients varied within the limit of +or- 2 kg. It produced a favorable lipid profile by increasing the mean level of high density lipoprotein (HDL) cholesterol and lowering the mean level of low density lipoprotein (LDL) cholesterol. The level of HDL cholesterol was 1.56 mmol/l in cycle 0 compared with 1.85 in cycle 6. The average level of LDL cholesterol was statistically lower in the 6th cycle of Marvelon use (2.73 mmol/l) in comparison to cycle 0 (3.29 mmol/l). Marvelon did not significantly influence the values of glucose, total cholesterol, and triglycerides. The Pearl Index was 0.0.

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The efficacy and acceptability of two third generation oral contraceptives in Thai women were evaluated in a prospective, open, group-comparative, randomized, multicenter trial of women asking for contraception. In six Family Planning Centers and Outpatient Gynaecological Clinics in urban areas in Thailand, 783 healthy women who were at risk for pregnancy and did not have contraindications to oral contraceptive use were randomly allocated to one of the two study groups. An oral contraceptive containing 30 mcg ethinylestradiol and 150 mcg desogestrel was given to 394 women and an oral contraceptive with the same amount of ethinylestradiol and 75 mcg gestodene to 389 women during 6 cycles. Criteria of cycle control, side effects and the presence and severity of acne vulgaris were assessed and blood pressure and body weight measured at pretreatment and after cycles 1, 3 and 6. Furthermore, the efficacy was evaluated after the last cycle. No pregnancies occurred with either of the contraceptives. The incidences of irregular bleeding and minor side effects in both groups were very low and decreased after an initial increase in the first cycle. Acne improved in both groups. Blood pressure and body weight remained unchanged. The two oral contraceptives were found to be effective and acceptable in Thai women. Compared to Caucasian women, the incidences of irregular bleeding and side effects were apparently lower in these Asian women. Furthermore, the effects of both oral contraceptives were comparable.

PIP: During October 1988-April 1990, clinicians randomly allocated 783 healthy women attending six family planning centers and outpatient gynecological clinics in urban areas of Thailand to either the group using a 30 mcg ethinyl estradiol (EE) combined oral contraceptive (OC) with 150 mcg desogestrel (DSG) (394 women) or an OC with 75 mcg gestodene (GSD) (389 women). Researchers aimed to evaluate the efficacy and acceptability of these two third-generation OCs. After six cycles of OC use, the continuation rate was 87.6% for DSG/EE and 85.9% for GSD/EE. No one from either group became pregnant. Women forgot to take the pills during 1.8% of the cycles with DSG/EE and 2% of the cycles with GSD/EE. Breakthrough bleeding was more common than spotting in both groups (0.8-5.4% vs. 0.6-2% for DSG/EE; 0.8-4.4% vs. 0-4.4% for GSD/EE), while in Caucasian women spotting was more common. Breakthrough bleeding and spotting rates were comparable in both groups. Irregular bleeding initially increased, then fell with time. Irregular bleeding for both OC groups was less common than it is in Northern European women. No one experienced any serious side effects. The most common minor side effects were nausea, headache, and breast tenderness. The incidences increased in the first cycle, then fell. They were comparable for both groups. Acne was less frequent after OC use (20.7% at baseline vs. 17.1% at 6 months for DSG/EE and 22% at baseline vs. 16.9% at 6 months for GSD/EE). Neither OC influenced the mean body weight or the mean blood pressure. These findings indicated that both OCs are very effective, provide excellent cycle control, and produce a low incidence of side effects. They also protect against acne.

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Two triphasic oral contraceptives containing either gestodene or norethindrone as the progestogenic compound combined with ethinyl estradiol were compared in a randomized clinical trial to assess their contraceptive reliability, clinical tolerance and cycle control. Both preparations were effective in preventing pregnancy. The gestodene preparation proved significantly superior regarding cycle control and general tolerance.

PIP: In Germany, researchers randomly placed 126 women into a group taking a triphasic oral contraceptive (OC) with gestodene and 128 women into another group taking triphasic norethindrone to do a 1-year controlled, multicenter open trial examining contraceptive efficacy, cycle control, and general tolerance. No one became pregnant during the study, despite mistakes in pill intake in 32 (2.5%) and 44 (3.7%) pill cycles of the gestodene group and norethindrone group, respectively. Women in the gestodene group experienced spotting at a higher rate than those in the norethindrone group (27% vs. 15.8%; p .05). The difference remained significant even when the researchers examined only 1st-time OC users (10.2% vs. 5%; p .05). On the other hand, breakthrough bleeding occurred less often in women in the gestodene group (19.3% vs. 29.6%). Over time, women in the norethindrone group were more likely to gain more than 2 kg than those in the gestodene group. Neither group experienced changes in blood pressure. Neither OC caused any serious adverse events, e.g., thromboembolism. The most common subjective adverse events were painful menstrual periods, breast tension, and headache. The incidence of acne increased in the norethindrone group. Adverse events were responsible for 3.5% of women in the gestodene group and 11.3% in the norethindrone group dropping out, sometimes citing more than 1 adverse event. Women in the norethindrone group were more likely to drop out because of adverse events than were those in the gestodene group (50% of all dropouts vs. 25%; p .05). Triphasic gestodene had better cycle control and was better tolerated than triphasic norethindrone. Weight gain and acne were less common in the gestodene group than the norethindrone group. In conclusion, triphasic gestodene is superior to that of triphasic norethindrone.

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The trend towards changing the composition of the contraceptive pill in order to decrease side effects might lead to increased ovarian activity. This may decrease reliability. Therefore, a non-invasive method for monitoring the suppressive effect of the pill on ovarian function is warranted. The aim of the present study was to investigate whether or not diagnostic ultrasound might be the method of choice for studying residual ovarian activity during pill use. In 89 women on a low-dose oral contraceptive (30 mcg ethinyl-estradiol (EE)/75 mcg gestodene), the first two months of pill-intake were monitored extensively with diagnostic ultrasound. The study revealed that only one ultrasound investigation was needed during the first week of pill intake to discover all relevant cases of residual ovarian activity. Follow-up investigations are needed to quantify this activity more specifically.

PIP: Physicians used ultrasound (Scanner 1150) on 89 women at medical centers in Maastrict in the Netherlands and Copenhagen in Denmark for 2 menstrual cycles to evaluate ultrasonography's scientific value in monitoring residual ovarian activity while women are taking low dose oral contraceptives (OCs). They performed transvaginal scanning in 89% of menstrual cycles and transabdominal scanning in the other cycles. They took blood samples to measure hormone levels and to compare these levels with ultrasound findings. The women used a low dose OC with 30 mcg ethinyl estradiol and 75 mcg gestodene. Ultrasound detected all cases of hormonally active ovaries as confirmed by serum ethinyl estradiol levels. The first ultrasound investigation conducted between pill intake days 0 and 4 revealed the highest proportion (13%, 23 of 176 cycles) of folliclelike structures (mean diameter, 18.9 mm). Between days 5 and 8, the proportion was still relatively high (12%) and the structures remained essentially the same size (18.3 mm). In 87% of the cycles with structures, the observed structures during the second investigation were likely the same structures observed in the first investigation. The third ultrasound investigation between days 10 and 12 detected continued folliclelike structures (mean diameter, 20.4 mm) in only 57% of women who had structures earlier. A rescan of women who did not have structures earlier did not detect any folliclelike structures, resulting in an overall proportion of cycles with structures of 7%. These findings suggested that ultrasound can reliably detect residual ovarian activity in women using low dose OCs, but the first ultrasound scanning should occur between days 0-7 to detect residual ovarian activity. Physicians should reexamine only those cases with structures greater than 10 mm every 2-4 days until they can determine the degree of ovarian activity. Should further studies confirm these findings, ultrasound monitoring could replace Pearl index studies to evaluate the efficacy of new hormonal contraceptives.

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PIP: Although there is no epidemiologic proof, combined oral contraceptives (OCs) containing the derivatives of third generation progestins seem to bring patients better likelihood of favorable long-term performance and reduced risk of vascular events. These third generation progestins include desogestrel, gestodene, and norgestimate. Health workers must remember that this risk was no longer the same as that of the first statistics of the Royal College of General Practitioners which made one afraid of even the OCs with lower levels of ethinyl estradiol and first and second generation progestins. In either case, numerous studies proved the excellent clinical tolerance and acceptability of third generation progestins by patients. By reason of these qualities, women over 40 can probably continue to use them except if they have contraindications related to a personal or genetic condition. On the other hand, an already observed comparison has occurred between the third generation progestins, no matter whether they originated from progesterone or derivatives of nortestosterone. The first generation progestins were considered as exercising a progestenic and estrogen agonist effect and having excellent metabolic tolerance. While the second generation progestins were appreciated for their anti-gonadotropic properties and anti-estrogenic powers, their adverse metabolic effects were feared. Today, the latest norpregnane derivatives are also endowed with powerful anti-gonadotropic capacities whereas the recent derivatives of nortestosterone have lost a very big part of their metabolic weaknesses. Improvement of the lipid profile that they determine, in association with ethinyl estradiol, can bring hope that recent OCs can even contribute to the improvement of the arterial condition, at least in certain women. For example, women with a history of thromboembolism may be able to use the norpregnane derivatives, which are still under development.^ieng

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PIP: Many publications have been dedicated to the mode of action, efficacy, and secondary effects of oral contraceptives (OCs). Healthy OC users neither accept side effects nor find them acceptable. In most, the level of effectiveness and the incidence of side effects are proportional to the total dose of steroids in the OC combination, the balance between the estrogen and progestin content, and the specific properties of the compounds. Cardiovascular events in OC users were first attributed to the ethinyl estradiol dose and, as a first step, the estrogen dose has been reduced in OCs produced since the 1970s. Next, the vascular risk has been correlated with changes in the lipid profile. Progestins with androgenic properties have been incriminated in unexpected vascular events because of their adverse effect on the lipid profile. In pursuit of minimizing these secondary effects and to favorably change lipid patterns, some new progestins without androgenic properties have been developed and are available in Europe. These new compounds, third generation progestins, are derived from levonorgestrel. These progestins belong to the gonane category and, because of their molecular structure, are capable of attaching themselves to the androgen receptor. They include gestodene, desogestrel, and norgestimate. The study of changes in the pattern of protein markers of the sex hormone binding globulin (SHBG) suggests very weak biological androgen activity when these progestins are administered with ethinyl estradiol. Likewise, the anti-estrogenic action of these progestins which have lost their partial androgenic effect is reduced. When these progestins are administered with the ethinyl estradiol, they do not obstruct the estrogenic effect on the level of protein markers, e.g., SHBG and high density lipoprotein. Although this effect is considered beneficial, the reduced estrogenic activity on antithrombin III, triglycerides, and perhaps target tissues may be considered a non-negligible disadvantage of the third generation progestins in the most recent OCs.^ieng

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Twenty-five women had their carbohydrate metabolism prospectively evaluated during the six months that they used a gestodene and ethinyl estradiol monophasic oral contraceptive. Serum glucose and insulin levels were measured during a 75-gram three-hour oral glucose tolerance test. At the six-month test, the three-hour glucose and the fasting and three-hour insulin values were significantly elevated. The literature on carbohydrate metabolism during gestodene oral contraceptive use is also reviewed.

PIP: The effects of combination-type oral contraceptives (OCs) (containing 75 mcg of the progestin gestodene and 30 mcg of ethinyl estradiol [EE] on carbohydrate metabolism during 6 months of use was evaluated in 25 women with a mean age of 26.1 +or- 1.1 years, parity of .7 +or- .1, and mean control weight of 143.5 +or- 6.1 pounds. An oral glucose tolerance test was performed after a 10-hour fast and a venous blood sample was taken. After drinking 75 g of glucose, repeat blood samples were drawn. After 6 cycles of OC use each subject was given another oral glucose tolerance test. The mean weight was 144.2 +or- 6.2 pounds. No complications and pregnancies occurred. The serum glucose 3-hour value was significantly elevated at the 6-month test. Also, significant increase of the fasting and 3-hour values of insulin were found. The results suggest that gestodene is capable of altering carbohydrate metabolism via its androgen receptor activity. Triphasic preparations (1650 mcg of gestodene and 680 mcg of EE) have a similar effect on carbohydrate metabolism as do monophasic pills (1575 mcg of gestodene and 630 mcg of EE) because of similar total steroid dose. OCs containing low-dose gestodene may alter carbohydrate metabolism to some extent but the longterm effects require further investigation as such new OCs have not been proved to be superior to existing formulations.

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In a large and open prospective multicenter trial of 12,250 cycles from 2,378 women, contraceptive efficacy, clinical tolerance and acceptability of a new monophasic contraceptive combination containing 75 mcg gestodene (delta-5-levonorgestrel) and 30 mcg ethinyl oestradiol were studied. The objective was to assess efficacy, safety, side effects and cycle control of this oral contraceptive on healthy women using no other additional birth control methods. Two women became pregnant (0.016%) during the trial; both were patient failures. There was no effect on systolic or diastolic pressures. An average weight increase of 0.3 kg was noted. Cycle control was excellent with 95% of the cycles free of spotting and 98% free of breakthrough bleeding after six cycles. No serious complications occurred. There was an overall incidence of 14% reported side effects (after six cycles), indicating that the hormonal combination is well tolerated. It should be noted that 41.4% of the patients had some complaint before starting the treatment. For all complaints, a highly significant improvement was seen during the treatment.

PIP: In a large and open prospective multicenter trial of 12,250 cycles from 2378 women, contraceptive efficacy, clinical tolerance, and acceptability of a new monophasic oral contraceptive (OC) containing 75 mcg gestodene (delta-5-levonorgestrel) and 30 mcg ethinyl estradiol (EE) were studied. The objective was to assess efficacy, safety, side effects, and cycle control for this OC on healthy women using no other additional birth control methods. 2 women became pregnant (0.016%) during the trial; both were patient failures. There were no side effects on systolic or diastolic pressure. An average weight increase of 0.3 kg was noted. Cycle control was excellent with 95% of the cycles free of spotting and 98% free of breakthrough bleeding after 6 cycles. no serious complications occurred. There was an overall incidence of 14% who reported side effects after 6 cycles, indicating that the hormonal combination is well-tolerated. It should be noted that 41.4% of the patients had some complaint prior to the start of treatment. For all complaints, a highly significant improvement was seen during treatment.

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The effects of a monophasic oral contraceptive (gestodene 75mcg + ethinylestradiol 30 mcg) on plasma glucose (PG) and insulin (IRI) responses to an oral glucose load (OGTT) and on glycosylated haemoglobin Alc (HbAlc), fructosamine (Fr), total cortisol (FT) and transcortin (CBG) were studied in 30 healthy women. Blood samples were taken before treatment and after 6 and 12 cycles. After 6 and 12 months, OGTT-PG and IRI levels showed substantially unchanged values; for HbAlc and Fr the same behaviour was seen with the exception of the latter between 6 and 12 months; FT and CBG showed significant rises. All recorded values were in the normal range. The basal and dynamic PG and IRI behaviour failed to show any significant variations between pre-treatment values and those after 6 and 12 months of OC administration. Other data showed a substantial neutrality for this oral contraceptive containing gestodene.

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RESUMEN

PIP: 69 healthy Mexican women using a new oral contraceptive (OC) containing 75 mcg of gestodene and 30 mcg of ethanol estradiol participated in a prospective study of the safety and efficacy of the method. All participants were evaluated on the s cycle day before beginning use and were questioned monthly about side effects and menstrual bleeding. 10 of the women were evaluated for cholesterol and triglyceride levels before use and after 4 and 8 months. The average age of the participants at admission into the study was 23.4 years. There were no pregnancies in 613 woman-months of use. The average blood pressure was 113.8 + or - 6.9 over 76.7 + or - 7.0 before use and 112.6 + or - 9.2 over 73.8 + or - 7.8 after 12 months of use. The average weight was 55.9 + or - 9.6 kg before use and 55.5 + or - 8.8 after 12 months of use. In the 1st treatment cycle 8 women reported spotting and 3 reported intermenstrual bleeding; the number reporting these signs gradually declined. The number reporting side effects was small and declined after the 1st treatment cycle. Dysmenorrhea declined significantly after the 1st cycle. The crude rate of termination was 44.9% after 1 year. 8 women (11.6%) terminated method use for reasons related to the method, including 2 for nausea and vomiting, 1 for nausea and dizziness, 2 for amenorrhea, and 1 each for intermenstrual bleeding, spotting, and increased blood pressure. Among the 10 women whose lipid and lipoprotein levels were tested, the average levels before and after 8 months respectively were 162.5 + or - 27.0 and 182.3 + or - 35.8 for total cholesterol, 86.5 + or - 29.5 and 120.0 + or - 45.0 for triglycerides, 45.7 + or - 9.3 and 60.6 + or - 6.5 for HDL cholesterol. In general these changes were not significant despite the tendency to increase especially of the triglycerides. The method thus appears to offer advantages for temporary fertility control among Mexican women.^ieng

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