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Drospirenone (DRSP) was synthesized as an analogue of spironolactone with the aim of producing a fourth-generation progestogen that differed from earlier progestogens in that it had antiandrogenic and little or no androgenic activity and lacked estrogenic effects while retaining some antimineralocorticoid activity. Since then, DRSP has been included in several oral contraceptive preparations together with an estrogen. However, increasing evidence has demonstrated that DRSP 4 mg on its own inhibits ovulation. It was thus a logical development to determine the efficacy of a tablet that only included DRSP 4 mg as an oral contraceptive. This proved successful and this product has now been approved by the Food and Drug Administration (FDA).

Administration of a low-estrogen combined oral contraceptive containing 0.15 mg d-norgestrel and 30 μg ethinyl estradiol per tablet to 268 Thai women for clinical study and in another group of 13 Thai women for metabolic study provided a satisfactory result. No effect of the treatment was observed on blood pressure, serum triglycerides, total serum cholesterol or liver function. However, minor changes in the body weight, oral glucose tolerance and serum insulin were observed. This oral contraceptive preparation seemed to gain the body weight and to show its acceptability and effectiveness, but a firm conclusion could not be drawn on either of them which was due to a high loss to follow-up in the study.

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 t...

Objective To conduct a systematic review evaluating the effectiveness of a folate-fortified oral contraceptive preparation in increasing blood folate concentrations to levels providing optimal protection against neural tube defects (> 906 nmol/L). Methods We searched Medline, EMBASE, Web of Science, and the Cochrane Library for human studies published from inception to June 2013 that evaluated oral contraceptive use and folate status. Case–control studies, cohort studies, and clinical trials were included. Efficacy and bioequivalence data were evaluated from included studies. Results Overall, efficacy and bioequivalence data for the folate-fortified oral contraceptive show that it is at least as effective as folic acid alone in raising blood folate concentrations, and that the concomitant administration of folate with the oral contraceptive component does not affect its absorption or kinetics. Conclusion A folate-fortified oral contraceptive preparation provides an option for women to maintain blood folate levels, especially those who may be planning a family after the cessation of oral contraceptive therapy.

Aim This 12-month study was conducted to evaluate the skeletal effects of two monophasic oral contraceptives containing 20 μg of ethinylestradiol and 100 μg of levonorgestrel (LEVO) or 150 μg of desogestrel (DESO). Methods Fifty-two women (18–24 years) were randomized into the DESO group or the LEVO group; 36 women served as controls. The areal bone mineral density (aBMD) of the femoral neck and the lumbar spine was evaluated by DXA, and parameters of bone geometry and volumetric bone mineral density (vBMD) were assessed by peripheral quantitative computed tomography at the distal radius and the tibia. Results The LEVO group did not lose vertebral aBMD, whereas women in the DESO group lost 1.5%. At the distal radius and the tibia (shank level, 14%), LEVO induced an increase in total cross-sectional area, indicating increased periosteal bone formation. Radial trabecular vBMD declined by 1.4±1.8% in the DESO group, while it remained unchanged in the LEVO group. Conclusion Our study suggests that the skeletal effects of OC preparations may be influenced by progestogenic components in young women.

Objectives: To evaluate the pattern of mineral density in eumenorrhoic and oligomenorrhoic perimenopausal women, and assess the effects of different low dose oral contraceptives (OC) on bone metabolism and spine bone density. Methods: Spine bone density was evaluated in a longitudinal 2-year follow-up, randomized, unblinded, uncontrolled clinical trial conducted in healthy, normally menstruating perimenopausal women, perimenopausal oligomenorrhoic women and in perimenopausal oligomenorrhoic women treated with an oral contraceptive containing 20 mcg ethinyl estradiol plus 0.15 mg desogestrel, 0.100 mg levonorgestrel, 0.75 mg of gestodene (n = 15 in each group). The results were analyzed by factorial or repeated measures analysis of variance, as appropriate. Results: During the observation period, in normal menstruating women there were no changes in menstrual cycle, plasma FSH and estradiol levels, and spine bone density. In oligomenorrhoic untreated women an increase in cycle length, with a concomitant decrease in plasma estradiol and an increase in plasma FSH levels were evidenced (p < 0.05). In this group a significant decrease in bone density (p < 0.05) occurred. In OC-treated women, a significant (p < 0.05) increase in bone density was observed, with no differences among different groups. Conclusion: Different progestins used in OC preparations do not modify the bone sparing effect of perimenopausal OC administration avoiding the decrease in bone density. © 2005 Published by Elsevier Ireland Ltd.

The effects of a common oral contraceptive preparation on the activity of 7 drug-metabolizing enzymes were investigated using the validated Cooperstown 5+1 Cocktail. In a randomized crossover fashion, 10 premenopausal women received caffeine, dextromethorphan, omeprazole, intravenous midazolam, and warfarin + vitamin K with and without a triphasic oral contraceptive (ethinyl estradiol 35 microg) and varying doses of daily norgestimate (0.18, 0.215, and 0.25 mg). Bioequivalence testing showed nonequivalence in drug versus no-drug treatment on the activity of drug-metabolizing enzymes (as reflected by metabolite ratios following probe drug administration); the activity of CYP1A2, CYP2C19, and NAT-2 decreased following the oral contraceptive, whereas the activity of CYP2C9 and CYP2D6 increased. No effects on xanthine oxidase or hepatic CYP3A were seen. Application of a non-parametric statistical testing approach revealed a significant difference only for CYP1A2 and CYP2C19. This triphasic oral contraceptive may have a clinically significant effect on the activity of some drug-metabolizing enzymes.

Recent use of oral contraceptive pills is associated with a modest risk of breast cancer among very young women. In this US population-based case-control study, we evaluated whether the excess risk associated with recent oral contraceptive use is ubiquitous for all pill types or attributable to specific oral contraceptive preparations. Hormonal content and potency of combination oral contraceptives used for the longest duration within 5 years of interview for breast cancer cases aged 20-44 years (N=1640) were compared with age-matched community controls (N=1492). Women who recently used oral contraceptives containing more than 35 microg of ethinyl oestradiol per pill were at higher risk of breast cancer than users of lower dose preparations when compared to never users (respective relative risks of 1.99 and 1.27, P(trend)

Sixteen normal healthy female volunteers, ages 22 to 42 years, participated in this study to determine the pharmacokinetic characteristics of zolpidem and the influence of oral contraceptives and smoking. Five of the volunteers were cigarette smokers, and 8 were on oral contraceptive preparations (OCP). All subjects received a 5 mg oral dose of zolpidem tartrate, followed by multiple blood samples that were assayed by HPLC with fluorescence detection. Among all subjects, mean apparent oral clearance was 376 ml/min (5.8 ml/min/kg), elimination half-life was 2.4 hours, and maximum serum zolpidem concentration was 60 ng/ml. Clearance was higher (445 vs. 345 ml/min) and half-life was shorter (1.8 vs. 2.7 h) in smokers than nonsmokers, although the differences were not statistically significant. Likewise, zolpidem clearance was higher and half-life shorter in women using OCP, but differences were not significant. Differences in zolpidem kinetics associated with smoking may be explained by the small contribution of cytochrome P450-1A2 to net clearance of zolpidem. In any case, the differences were quantitatively small and not likely to be of clinical importance.

Desogestrel (DSG) is a third-generation 19-nortestosterone derivative progestogen. It is contained in many oral contraceptive preparations, both combined (COCs) to ethinyl-estradiol (EE) or alone in a progestin-only pill (POP). Its principal metabolite (etonogestrel, ETN) is the only progestin used for intravaginal combined contraception and one of the most used for subdermal hormonal contraception.This is a review of the available data on the pharmacokinetics of DSG and ETN in hormonal contraception. The material included was searched and obtained via Medline, PubMed, and EMBASE up to July 2013 using the search terms 'pharmacokinetics, metabolism' in combination with 'desogestrel, etonogestrel, and progestins.'DSG and its metabolite ETN are very suitable molecules for use in hormonal contraception. For the oral use the molecule used is DSG, while for parenteral routes (intravaginal, subdermal) its metabolite ETN is the compound of choice. In both cases (oral and parenteral) the active molecule in the organism is the latter (ETN), due to the rapid in vivo metabolism of oral DSG. The contraceptive efficacy and tolerability of all the formulations present on the market (mono/multiphasic EE/DSG COCs, DSG POP, EE/ETN vaginal ring, ETN implant) are reassuring, permitting a long-term use. The estrogenic component increases the contraindications, forcing the prescription to the safer only-progestin preparations, DSG POP or ETN implant.

Menstrual cycle has an influence on mind and body of any woman. A collection of symptoms that emerges one or two weeks before menstruation begins is called premenstrual syndrome (PMS), and that involves variety of complex emotional and physical changes. However, aggravation of epileptic attacks during premenstrual period alone has been focused in women with severe motor and intellectual disabilities (SMID). Exacerbation of various symptoms, other than epilepsy, was recognized as PMS in five cases, and these include muscular hypertonia, fever, tachycardia, flushing on face, nausea and vomiting. In these cases, the PMS symptoms were successfully managed with the low-dose oral contraceptive preparations. PMS among patients with SMID are often found to be difficult to diagnose. The use of the low-dose oral contraceptive was effective in women with SMID and improve the quality of their lives (QOL).

This study compares the contraceptive reliability, cycle control, and tolerability of two oral contraceptive preparations containing 20 micrograms of ethinyl estradiol combined with either 75 micrograms of gestodene (EE/GSD) or 150 micrograms of desogestrel (EE/DSG). Women received the trial preparations daily for 21 days, followed by a 7-day pill-free interval. Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of 12 cycles. Efficacy data of 14,700 treatment cycles (EE/GSD: 7299; EE/DSG: 7401) were obtained from 1476 women (EE/GSD, n = 740; EE/DSG, n = 736). Both preparations provided effective contraception and good cycle control with a similarly low incidence of both spotting and breakthrough bleeding. The spotting rates in both treatment groups decreased from 35.1% (EE/GSD) and 37.5% (EE/DSG) in the first treatment cycle to approximately 10% in the fourth treatment cycle. The spotting incidence as percent of the total number of cycles was 12.7% for EE/GSD and 14.3% for EE/DSG. The breakthrough bleeding incidence was 5.2% of all cycles for EE/GSD and 6.0% of all cycles for EE/DSG. For 84.7% of the cycles in the gestodene group and for 82.5% of the cycles in the desogestrel group, neither spotting nor breakthrough bleeding were recorded. Overall, the spotting and breakthrough bleeding incidence tended to be lower with EE/GSD than with EE/DSG. However, the difference was not statistically significant. Amenorrhea was recorded in 2.7% of the cycles with EE/GSD and in 2.9% with EE/DSG. Both preparations were well tolerated and showed a similar pattern of adverse events. More than 83% of the women in both groups either did not gain weight or lost more than 2 kg. Both preparations had a beneficial effect on dysmenorrhea. Both regimens provided reliable contraception and good cycle control. The incidence of adverse events was relatively low and both preparations were well tolerated.This study compares the contraceptive reliability, cycle control, and tolerability of two oral contraceptive preparations containing 20 mcg of ethinyl estradiol combined with either 75 mcg of gestodene (EE/GSD) or 150 mcg of desogestrel (EE/DSG). Women received the trial preparations daily for 21 days, followed by a 7-day pill-free interval. Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of 12 cycles. Efficacy data of 14,700 treatment cycles (EE/GSD: 7299; EE/DSG: 7401) were obtained from 1476 women (EE/GSD, n = 740; EE/DSG, n = 736). Both preparations provided effective contraception and good cycle control with a similarly low incidence of both spotting and breakthrough bleeding. The spotting rates in both treatment groups decreased from 35.1% (EE/GSD) and 37.5% (EE/DSG) in the first treatment cycle to approximately 10% in the fourth treatment cycle. The spotting incidence as percent of the total number of cycles was 12.7% for EE/GSD and 14.3% for EE/DSG. The breakthrough bleeding incidence was 5.2% of all cycles for EE/GSD and 6.0% of all cycles for EE/GSD. For 84.7% of the cycles in the gestodene group and for 82.5% of the cycles in the desogestrel group, neither spotting nor breakthrough bleeding were recorded. Overall, the spotting and breakthrough bleeding incidence tended to be lower with EE/GSD than with EE/DSG. However, the difference was not statistically significant. Amenorrhea was recorded in 2.7% of the cycles with EE/GSD and in 2.9% with EE/DSG. Both preparations were well tolerated and showed a similar pattern of adverse events. More than 83% of the women in both groups either did not gain weight or lost more than 2 kg. Both preparations had a beneficial effect on dysmenorrhea. Both regimens provided reliable contraception and good cycle control. The incidence of adverse events was relatively low and both preparations were well tolerated.

This review addresses current knowledge of the effects of lower dose oral contraceptives (containing 35, 30, or 20 micrograms of ethinyl estradiol) on hemostasis in smoking and nonsmoking women. Evidence suggests that formulations containing 30 and 35 micrograms ethinyl estradiol induce a significant activation of coagulation, whereas oral contraceptive preparations with 20 micrograms ethinyl estradiol appear to have a negligible effect or no effect. In nonsmokers who take oral contraceptives any procoagulatory effects that may occur are counterbalanced by fibrinolytic effects. In smokers, however, compensatory fibrinolytic effects to offset the procoagulatory effects seen with 30-micrograms ethinyl estradiol oral contraceptive formulations are absent, shifting the hemostatic profile toward a hypercoagulable state. This suggests that a formulation with the lowest dose of ethinyl estradiol may be most suitable for smokers who wish to use this form of contraception.This review addresses current knowledge of the effects of lower-dose oral contraceptives (OCs) (containing 35, 30, or 20 mcg of ethinyl estradiol) on hemostasis in smoking and nonsmoking women. Data showed that the OCs containing 30-35 mcg ethinyl estradiol influence a significant activation of coagulation parameters compared to the 20-mcg formulations, which appear to have little or no procoagulatory effect. However, procoagulatory effects of these OCs showed to be counterbalanced by the compensatory anticoagulation effects within the fibrinolytic system. This would indicate that most healthy women taking lower-dose OCs, particularly those containing 20 mcg ethinyl estradiol, are not at increased risk for thromboembolic disease. However, this compensatory activity of the fibrinolytic system does not occur in women who both smoke and use OCs. Studies documented that simultaneous smoking and OC use could lead to hypercoagulation. This suggests that OCs with the lowest effective dose of ethinyl estradiol are the best contraceptives for smokers.

Cycle control and tolerability of two monophasic oral contraceptive pills containing 30 microg ethinyl estradiol (EE) with either 150 microg desogestrel (DSG) or 75 microg gestodene (GSD) were compared in women starting oral contraception. A minimum of 200 healthy women at risk for pregnancy were to be treated for a total of 6 cycles per patient in a prospective, randomized open parallel-group multicenter trial. Two hundred and forty-one subjects were randomized, 115 to DSG/EE and 126 to GSD/EE. Compliance to the study preparation was high (around 95%) in both groups and no pregnancies occurred during the study. Cycle control was excellent; there were no differences between the two groups with regard to incidence of spotting and breakthrough bleeding or duration and intensity of withdrawal bleeding. Side-effects were mild and in general comparable in the two groups. Both at baseline and during treatment, a higher proportion of women taking GSD/EE complained about breast tenderness. This resulted in more early withdrawals because of breast tenderness in the GSD/EE group. It was concluded that monophasic DSG/EE and GSD/EE are equally effective, have similar cycle control and both are generally well tolerated.

Objectives To determine the effect of two low-dose monophasic oral contraceptives containing either 2 mg chlormadinone acetate or 150 μg desogestrel on blood clotting and fibrinolysis.Methods In vivo markers of intravascular coagulatory and fibrinolytic activity were measured in 45 volunteers randomly assigned to a 6-month treatment with one of the two study preparations.Results During oral contraceptive use, the procoagulatory activity increased (increased prothrombin fragment 1+2), the anticoagulatory capacity changed (increased protein C activity, decreased activated protein C sensitivity, decreased protein S activity and decreased antithrombin III activity) and the fibrinolytic system was activated (increased concentrations of plasmin-antiplasmin complexes and d-dimer as well as total fibrin degradation products). There were no relevant differences between the two medication groups.Conclusion Our results demonstrate that both oral contraceptive preparations have comparable effects on the hemostatic sy...

Efforts by governments and public health bodies largely have been unable to reduce cigarette consumption by Canadians. Women who smoke (29% of women in the reproductive years) have reduced fertility and an increased risk of short-term and long-term cardiovascular disease. Women who have used oral contraceptive preparations in the past appear to have no increased cardiovascular risk, but current users carry an increased risk of thrombosis. The degree of risk is proportional to the estrogen dose of the preparation used. Women who smoke cigarettes and concurrently use oral contraceptives increase their risk of myocardial infarction beyond that of using either agent alone; the risk is increased in heavier smokers and in women over age 35. There is no effect of smoking on other forms of contraception.

Introduction It is a commonly held belief that combined oral contraceptive (COC) pills containing an androgenic progestin may be less likely to impair sexual function than COCs containing an anti‐androgenic progestin. Aim The study aims to compare the effects of a COC containing a progestin with an anti‐androgenic profile (estradiol valerate [E 2 V]/dienogest [DNG]) to that of one with an androgenic progestin (ethinyl estradiol [EE]/levonorgestrel [LNG]) on sexual function in women with COC‐associated sexual dysfunction. Methods In this multicenter, randomized, double‐blind, noninferiority study, women with COC‐associated female sexual dysfunction (FSD) were randomized to E 2 V/DNG or EE/LNG for six cycles. The primary outcome was the change in the sum of Female Sexual Function Index (FSFI) desire and arousal component scores between baseline and cycle 6. Secondary outcome measures included changes to the FSFI domains, the Female Sexual Distress Scale (FSDS‐R), Vaginal Health Assessment, the Atrophy Symptom Questionnaire, and the Psychological General Well Being Index over six treatment cycles. Main Outcome Measure The main outcome is the change in the sum of FSFI desire and arousal component scores between baseline and cycle 6. Results Of 276 women screened, 213 received treatment and 191 completed the study. The mean increase in the sum of FSFI desire and arousal component scores was 5.90 (standard deviation [SD] 5.45) for E 2 V/DNG and 5.79 (SD 6.17) for EE/LNG (change from baseline P Conclusion In women with COC‐associated FSD, switching to either E 2 V/DNG or EE/LNG was associated with equivalent improvements in symptoms, challenging the perception that COCs containing anti‐androgenic progestins have a detrimental effect on sexual function relative to those containing androgenic progestins. Davis SR, Bitzer J, Giraldi A, Palacios S, Parke S, Serrani M, Mellinger U, and Nappi RE. Change to either a nonandrogenic or androgenic progestin‐containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive‐associated sexual dysfunction. J Sex Med 2013;10:3069–3079.

The efficacy, tolerability and cycle control of a monophasic oral contraceptive preparation containing gestodene (75μg) plus ethinylestradiol (30 μg) (Minulet®) were studied in 139 women aged over 35 years (mean age 37.12 ± 2.47 years) in a prospective, open-label, non-comparative study. Each subject received one tablet daily for 21 days followed by 7 days without medication, for six cycles. Of the 809 cycles studied, 96.04% had normal withdrawal bleeding, without breakthrough bleeding or spotting. The mean menstrual cycle length and duration of withdrawal bleeding were similar before and after treatment. The percentage of severe withdrawal bleeding cycles was reduced and the percentage of mild withdrawal bleeding cycles increased following treatment. No incidence of amenorrhea was observed and no pregnancies were reported. Five subjects withdrew due to adverse events. The most frequent symptoms reported during the study were breast tenderness, headache, nausea, nervousness and depression. Minulet, a low-...

The newer progestogens gestodene, desogestrel and norgestimate were developed in an attempt to produce agents with more selective progestational activity that would improve cycle control and minimise metabolic changes and adverse events while effectively preventing pregnancy. In clinical practice, gestodene is combined with ethinylestradiol in monophasic or triphasic combined oral contraceptive preparations. The drug has pharmacokinetic advantages over the other new progestogens in that it is active per se (the others are prodrugs) and has high bioavailability (approximately 100%). The ability of gestodene-containing oral contraceptives to inhibit ovulation is similar to that of preparations containing other progestogens although the required dosage is lower. In common with oral contraceptives containing desogestrel or norgestimate, and in contrast with those containing levonorgestrel, gestodene-containing preparations are associated with neutral or positive changes in lipid and carbohydrate metabolism. The effects of gestodene preparations on coagulation parameters, like those of desogestrel and levonorgestrel, are balanced by changes in the fibrinolytic system. Although the impact of these changes on clinical cardiovascular end-points has not been determined, the altered lipid profile is not likely to have significant clinical relevance because of the predominantly thrombogenic nature of cardiovascular disease in oral contraceptive users. Pregnancy rates and Pearl Indices with gestodene-containing preparations are low and similar to those with preparations containing other progestogens. Most pregnancies are attributable to user failure. Cycle control appears to be better with gestodene preparations than with levonorgestrel preparations, and available data suggest that cycle control may also be better with monophasic gestodene/ethinylestradiol than with monophasic desogestrel- or norgestimate-containing preparations, and better with triphasic gestodene- than with triphasic levonorgestrel- or norgestimate-containing preparations. However, differences between the new progestogen-containing preparations need to be confirmed in further large-scale trials. The most common adverse events with gestodene/ethinylestradiol are headaches and breast tension; the incidence of short term adverse events, including acne, is similar to that with preparations containing other progestogens. Changes in blood pressure and bodyweight are negligible. There are no comparative data on the incidence of cardiovascular events with gestodene-containing and other combined preparations. While the risk of breast cancer appears to be increased with long term combined oral contraceptive use in certain patient subgroups, this risk needs to be balanced against the noncontraceptive benefits of these preparations.(ABSTRACT TRUNCATED AT 400 WORDS)

The triphasic levonorgestrel oral contraceptive preparation was introduced in the late 1970s and today it is available in more than 90 countries. The substantial volume of clinical experience now available has established that not only is this preparation clinically effective but that it also provides excellent cycle control. In this paper, results of efficacy, cycle control and patient acceptability/compliance are reviewed, drawing together the considerable clinical experience that now exists.All studies confirm the contraceptive reliability of triphasic levonorgestrel and report good patient compliance. Good patient compliance is, in part, due to the low incidence of breakthrough bleeding and spotting (intermenstrual bleeding) as well as the low incidence of failure of withdrawal menses (amenorrhea) that is achieved with this oral contraceptive, even in the first few cycles. The side-effect profile of triphasic levonorgestrel is also good and most studies report it to be well tolerated. When compared bo...

Objective To review the etiology, pathogenesis, diagnostic approach, and management of hirsutism. Methods We discuss the clinical course of hirsutism and provide our recommendations on the various treatment options available. Results Hirsutism is a common clinical problem characterized by the presence of increased terminal hair growth in androgen-dependent areas of the skin. The development of hirsutism depends on the presence of the pilosebaceous unit, which is genetically determined, as well as the presence of the androgen receptor and intracellular 5α-reductase activity, which converts testosterone to its more active metabolite, dihydrotestosterone. A detailed history and physical examination and the following laboratory tests can diagnose most causes of hirsutism: early-morning follicular phase measurement of total testosterone, testosterone not bound to sex hormone-binding globulin, dehydroepiandrosterone sulfate, 17-hydroxypro- gesterone, prolactin, and thyrotropin levels. Oral contraceptive preparations may be effective monotherapy for mild hirsutism. For the treatment of more severe hirsutism, oral contraceptive pills combined with spironolactone are as effective as oral contraceptive pills containing cyproter- one acetate, which are not available in the United States. Because of teratogenicity, spironolactone should be used with caution in premenopausal women when it is administered without an oral contraceptive pill. Metformin is an alternative therapy for hirsutism in women with polycystic ovary syndrome who have other indications for metformin use. Metformin is not as effective as antiandrogens for the management of hirsutism. The use of glucocorticoids, finasteride, or flutamide is not recommended. Conclusions Hirsutism can be evaluated with a detailed history and physical examination and a limited number of hormonal tests. Serious disorders presenting as hirsutism are rare and can be excluded with the recommended evaluation. Treatment is targeted at reducing the production and bioavailability of testosterone, as well as blocking target tissue androgen action. (Endocr Pract. 2011;17:807-818)

This report combines the data obtained in three multicenter efficacy studies with a new triphasic oral contraceptive combination containing desogestrel (DSG) and ethinyl estradiol (EE). The studies were conducted at 40 investigational sites in the United States (38 centers) and Canada (2 centers) in support of the FDA approval of the product. In total, 1,095 subjects were exposed to the study medication for 11,231 cycles, corresponding to approximately 864 woman-years of use. Of these subjects, 414 completed at least 13 cycles of treatment. Contraceptive efficacy was high; six pregnancies occurred during the in-treatment period (two due to method failure and four due to user failure), corresponding to Pearl Indices of 0.23 and 0.46, respectively. The incidence of irregular bleeding was low, and the acceptability was excellent as evidenced by the low incidence of drug-related drop-outs. No drug-related serious adverse experiences were reported, and the incidence of other drug-related adverse experiences was generally low and decreased with continued use. No effects were seen on blood pressure, body mass index, laboratory parameters, cervical cytology and breast nodularity. These studies demonstrate that triphasic DSG/EE is an effective and acceptable triphasic oral contraceptive preparation with excellent cycle control and no significant physiologic effects.

This trial was designed to determine the differences in effectiveness, clinical acceptability, and one-year discontinuation rates of two low-dose oral contraceptives: Lo-Estrin (norethindrone acetate 1.5 mg plus ethinyl estradiol 0.030 mg) and Lo-Femenal (norgestrel 0.30 mg plus ethinyl estradiol 0.030 mg) in 148 Mexican women. In addition, the effects of both oral contraceptive preparations on blood lipids were prospectively evaluated in a subgroup of 41 women. The results indicated that there were no differences in pregnancy rates, discontinuation or clinical acceptability between the two groups. The lipid changes observed were minimal for the Lo-Femenal subgroup and somewhat greater for the Lo-Estrin group, mainly an increase in serum triglycerides. These changes were interpreted as estrogen induced effects of norethindrone-containing oral contraceptives. Overall, the data indicate that both Lo-Femenal and Lo-Estrin are effective and safe combined oral contraceptives.

The hormonal components of oral contraceptives exert major effects on plasma lipoprotein metabolism. Estrogens may increase production of plasma triglycerides, leading to increased levels of very low-density lipoproteins, but they may also reduce levels of cholesterol-enriched and potentially atherogenic intermediate- and low-density lipoproteins. Furthermore, estrogens increase levels of high-density lipoproteins (HDLs), particularly the HDL2 subspecies, an effect linked to reduced mortality rates from cardiovascular disease in postmenopausal women receiving hormone replacement therapy. All combination oral contraceptives in use in the United States tend to raise levels of plasma triglycerides, low-density lipoprotein, and HDL3 to varying degrees. In contrast, changes in HDL and HDL2 reflect the combined effects of estrogen dose and relative androgenicity of the progestin component. Although in general, the lipoprotein changes are greater in magnitude with higher dose oral contraceptive preparations, they can be significant in lower dose preparations as well. Oral contraceptives also affect carbohydrate metabolism, primarily through the activity of progestin. Studies have demonstrated insulin resistance, rises in plasma insulin, and relative glucose intolerance by means of curve analysis of glucose tolerance tests. These effects are far less pronounced with lower dose preparations and with formulations using the newer progestins.Many preclinical and clinical studies reveal that changes in lipoprotein metabolism are a major contributing factor to atherosclerosis. Hormones in oral contraceptive (OC) formulations strongly influence lipoprotein metabolism. Specifically, estrogens bring about increases in plasma triglycerides which then cause a rise in the very low density lipoprotein. They also decrease levels of the intermediate and low density lipoprotein which cause build up of plaque on arterial walls. Estrogens also lead to rising high density lipoprotein (HDL) levels, especially the HDL2 subspecies. Increased HDL levels are associated with lower mortality rates from cardiovascular conditions in women who have already experienced menopause and are on hormone replacement therapy. Combination OCs used in the US increase plasma triglycerides, low density lipoprotein, and HDL3. The estrogen dose and the relative androgenicity of the progestin together influence the changes in HDL and HDL2. Even though low dose combined OCs bring about lipoprotein changes which are lower than those of higher dose OCs, the changes often remain significant. The progestin component of OCs is responsible for most changes in carbohydrate metabolism. Specifically OC use can lead to increased levels of plasma insulin, insulin resistance, and relative glucose intolerance. A curve analysis of glucose tolerance tests reveals this intolerance effect of OCs. The changes in carbohydrate metabolism are not as great in women using the lower dose OCs or formulations using the new progestins, however.

Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.51 hirsute women were randomly treated for 9 months with ethinyl estradiol (EE) 35 mcg + norethindrone 0.4 mg or 30 mcg EE + 1.5 mg norethindrone acetate if contraception was necessary or spironolactone 200 mg daily if it was not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the 2 oral contraceptives (OCs) but not with spironolactone. While systolic blood pressure was lower with it, fasting insulin levels were higher as opposed to either low-dose OC preparation. EE 30 mcg + 1.5 mg norethindrone acetate lowered 3-alpha-diol-glucuronide levels; however, E 35 mcg + norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

Erythrocyte Cu, Zn-superoxide dismutase activity (SOD), ceruloplasmin activity (CP) and serum copper concentration (SCu) were determined in normal adult males (n=239) and females (n=145). The effects of age, smoking, drinking frequency, exercise and oral contraceptive use or estrogen replacement therapy on these indices of copper status were investigated. For males, the mean SOD (U/mg hemoglobin±SD) was 77.42±15.7 and for females, 75.7±19.9. CP and SCu were highly correlated, while no significant relationship between these two indices of copper status and SOD could be detected. Both SCu and CP varied significantly with age in females but not in males. No age-related differences in SOD were found. Estrogen use, both in oral contraceptive preparations by pre-menopausal women and as replacement therapy by postmenopausal women significantly increased both SCu and CP but had no effect on SOD. Smoking, drinking frequency and activity level had no significant effect on any of these parameters of copper status.

The influence of a triphasic oral contraceptive preparation on plasma lipid, lipoprotein, and apolipoprotein levels was studied in 20 women during 12 treatment cycles. Multiple blood samples representing all phases of the therapeutic cycle as well as posttherapy were obtained. Total and low-density lipoprotein (LDL) cholesterol fluctuated transiently in the earlier part of the study but after 9 and 12cycles of therapy did not differ from baseline. Cyclic elevations in total cholesterol corresponding to changes in LDL cholesterol were noted twice. Total high-density lipoprotein (HDL) cholesterol remained remarkably stable over the entire study while HDL 2 cholesterol decreased and HDL 3 cholesterol increased. Triglycerides (total and lipoprotein fractions) increased during treatment and fell to baseline levels within one posttreatment cycle. Very low-density lipoprotein (VLDL) cholesterol was also elevated during the study. Apolipoprotein (apo) AI, apo AII, and apo B rose under therapy, the latter increase producing a lowered LDL cholesterol/apo B ratio. Apolipoprotein E showed a temporary decrease early in the study but otherwise remained unchanged.

The effects of two third-generation monophasic combined oral contraceptives (COC) and a postmenopausal hormone replacement therapy (HRT) consisting of 2 mg 17 beta-oestradiol on the plasma level of the acute-phase indicator C-reactive protein (CRP) and other acute-phase reactants were analysed. Two studies were conducted: (1) a randomised, open-label study with two different oral contraceptive preparations with an equal dose of ethinylestradiol (30 micrograms) and a different progestogen, either 75 micrograms gestodene (GSD-EE) or 150 micrograms desogestrel (DSG-EE); blood samples of 39 young women were analysed before and after 3, 6, 12 treatment cycles; (2) a randomised, blinded placebo-controlled study with 2 mg 17 beta-oestradiol in postmenopausal women with non-insulin-dependent diabetes mellitus without signs of cardiac involvement; blood samples of 38 women were analysed before and after 6 weeks of treatment. The plasma concentration of CRP increased strongly during oral contraceptive use for both preparations; the increase persisted over 12 cycles. The already elevated CRP in postmenopausal diabetic women showed a moderate increase after 6 weeks of treatment with 17 beta-oestradiol. CRP increases during oral contraceptive use were associated with changes in some other acute-phase proteins (fibrinogen, ceruloplasmin, von Willebrand factor [vWF]) originating from the liver and vessel wall, but not in others (interleukin-6 [IL-6], serum amyloid A [SAA]). The results demonstrate an increase in a specific set of acute-phase reactants caused by oestrogen-containing preparations. It is proposed that the pro-inflammatory effect of oestrogens should be checked for a relationship with the increased risk of thromboembolism for both oral contraceptive and HRT.

Oral contraceptives (OC) are a definite risk for venous thrombosis. It is commonly accepted that they cause a fourfold increased risk of thrombosis compared to non-users. The prescription patterns were evaluated from 1990 to 2000 in a northern Italian province (province of Padua). This province is typical of other northern Italian provinces. As a consequence, it can be safely assumed that the observations gathered may apply to the entire north of Italy. During these years, a sharp increase in the use of OC was noted. Furthermore, around 1995 to 1996, a marked switch toward the use of preparations containing third-generation progestins was noted. During the past few years of the observation period, approximately 80% of women use preparations containing third-generation progestins. During the same period, an increased incidence of episodes of venous thromboembolism (VTE) was noted. The increase in the prevalence of VTE episodes appeared to be proportional to the increased use of OC, regardless of the type of progestin contained in the oral contraceptive preparations.

The evaluation of the study was of the impact of oral contraceptive (OC) use on activated protein C (APC-resistance). Eight hundred eighteen young fertile women were screened for a study designed to compare three different marketed OC preparations. The women could have used either other oral contraceptive preparations before switching to the study medications (switchers) or were not using hormonal contraceptives (new starters) before the study began. Prior to study drug intake and during treatment, APC-resistance was determined with three different tests. Forty-one of 809 women evaluated (5.07%) carried the Factor V Leiden mutation. Twenty-two further participants (2.72%) had a positive screening test, but did not provide samples for the confirmatory mutation test. Two women with homozygous Factor V Leiden mutations and 39 women with heterozygous mutations were identified. The homozygous carriers were identified in all three of the screening tests employed, whereas none of the tests detected all 39 heterozygotes. In the pretreatment screening tests, previous OC users (switchers) had slightly lower APC ratios than the women using non-hormonal birth control methods (starters). During treatment the difference between starters and switchers was no longer apparent, but the APC ratio values of the screening tests slightly increased for both. The homozygous carriers were not treated. Differences in APC-resistance between users of the three different oral contraceptive preparations were not found. In conclusion, laboratory screening for APC-resistance using Coatest APC, ProC Global, or ProC APC-FV-Leiden clearly identifies homozygous mutant carriers. However, with regard to heterozygous mutant carriers, the sensitivity and specificity of the tests, especially during OC intake, is limited. The results of APC screening tests should have, at present, no impact on contraceptive counseling because the predictive value for thromboembolic risk of the test results and even the mutant status is low.

A comparison of cycle control, efficacy and tolerability of two oral contraceptive preparations containing 20 microg ethinylestradiol combined with either 100 microg levonorgestrel (EE/LNG 20/100) or 500 microg norethisterone (EE/NET 20/500) was conducted. These results were compared to a standard reference preparation, containing 30 microg ethinylestradiol combined with 150 microg levonorgestrel (EE/LNG 30/150). Efficacy data from 8,544 treatment cycles were obtained from 767 women. Good cycle control and effective contraception was achieved with the two LNG preparations, however, the cycle control results were less favorable with EE/NET 20/500. The cumulative incidence of women with at least one episode of intermenstrual bleeding from cycles 2 to 7 (primary target variable) was 43.9% for EE/LNG 20/100, 72.7% for EE/NET 20/500, and 15.7% for the standard EE/LNG 30/150. The difference between the 2 20 microg of EE preparations, which favored EE/LNG 20/100, was statistically significant (p = 0.001). The overall spotting rates (cycles 1-13) were 9.3% for EE/LNG 20/100, 21.7% for EE/NET 20/500, and 3.3% for the standard EE/LNG 30/150. Amenorrhea was reported in 7.1% (EE/LNG 20/100), 20.6% (EE/NET 20/500), and 0.9% (standard EE/LNG 30/150), respectively. Intermenstrual bleeding episodes were shorter with EE/LNG 20/100 and EE/LNG 30/150 of the 13 treatment cycles. The study Pearl indices were 0.9 for EE/LNG 20/100, 1.9 for EE/NET 20/500, and 0.0 for EE/LNG 30/150. All three treatments were well tolerated. However, tolerability was somewhat less favorable with EE/NET 20/500. A total of 160 women prematurely discontinued the study for various reasons (EE/LNG 20/100: 7%; EE/NET 20/500: 18%; EE/LNG 30/150: 4%). The overall adverse event incidence rate during the trial was low in all groups. Blood pressure remained largely unaffected. Thirteen serious adverse events were recorded for all treatment groups, all but one were assessed as not related to the treatments. There were no remarkable treatment related differences in mean body weight throughout the study and the laboratory values were largely unaffected in all three treatments groups.

Editor,—We were pleased to see the publication on behalf of the UK Steering Group “Recommendations for the management of galactosaemia”.1 In particular, we were pleased to see the emphasis on the management of adult women and the prevention of osteoporosis. We have, however, some concerns about the advice on the use of Loestrin 20 (an oral contraceptive preparation containing 20 μg ethinyl oestradiol and a progestogen) for long term oestrogen replacement. None of the combined oral …

Carbohydrate metabolism was evaluated in 17 women before and after 18 months of triphasic oral contraceptive use. The triphasic oral contraceptive contained levonorgestrel and ethinyl estradiol. An oral glucose tolerance test was utilized and both plasma glucose and insulin levels were measured. There were no significant changes in the glucose levels. The fasting insulin level was raised at the 18-month test, whereas the other insulin values were similar. These results demonstrate that the new triphasic oral contraceptive preparations produce minimal carbohydrate metabolic changes.

The aim of this 24-cycle study was to evaluate the effects on serum lipid concentrations of an oral contraceptive preparation containing 100 microg levonorgestrel and 20 microg ethinyl estradiol.Forty-two healthy women were enrolled in a study designed to evaluate the effects on serum lipid concentrations of an oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol. Lipid data were evaluated for 28 women who completed 24 cycles of treatment with a preparation of 100 microg levonorgestrel with 20 microg ethinyl estradiol for 21 days followed by placebo for 7 days. Concentrations of triglycerides, total cholesterol, high-density lipoprotein cholesterol, high-density lipoprotein cholesterol subfractions 2 and 3, low-density lipoprotein cholesterol, and apolipoproteins A-I and B were analyzed. Mean percentage changes from baseline were tested for significance by means of paired Student t tests.Total cholesterol, high-density lipoprotein cholesterol, high-density lipoprotein subfraction 2, and apolipoprotein A-I concentrations were not significantly changed from baseline. Neither was the ratio of high-density lipoprotein subfraction 2 to high-density lipoprotein subfraction 3. Mean percentage increases in concentrations of triglyceride, high-density lipoprotein subfraction 3, apolipoprotein B, and low-density lipoprotein cholesterol and increases in the ratios of total cholesterol to high-density lipoprotein cholesterol, low-density lipoprotein cholesterol to high-density lipoprotein cholesterol, and apolipoprotein B to apolipoprotein A-I were significant (P.05) at/=1 cycle. By cycle 24, however, only the concentration of high-density lipoprotein subfraction 3 remained significantly elevated.Changes in the plasma lipid profiles among women receiving monophasic 100 microg levonorgestrel with 20 microg ethinyl estradiol were similar to those seen with other low-dose oral contraceptives, but by cycle 24 only 1 of 7 mean values remained significantly different from baseline.

Several papers and surveys have demonstrated regardless of the oral contraceptive (OC) involved an increased incidence of arterial thrombosis mainly strokes and myocardial infarction (MI) in smokers on OC. Women on oral contraception who are heavy smokers have approximately a 30-fold increase in MI as compared to nonsmoking non-users. A few years ago a new progestin (Yasmin) drospirenone 3 mg was proposed in combination with 30 lg of ethinestradiol as a "new and safe oral contraceptive preparation". It seems safe to underscore that smokers even moderate ones should abstain from OC intake or vice versa should stop smoking while on the medication. This advise is valid for all contraceptives but seems especially so for drospirenone-containing preparations. (excerpt)

Endometriosis is a major womens health-care problem. It causes pain and/or infertility and affects millions of women worldwide. Endometriosis is defined according to histological criteria by the presence of tissue resembling endometrium in sites outside the uterus most commonly the ovaries and peritoneum. The aim of treatment has been to remove the deposits of ectopic endometrium that are thought to be responsible for the symptoms of endometriosis. This can be achieved surgically by destroying or removing the implants; medical therapies induce atrophy within the hormonally-dependent ectopic endometrium. The duration of hormonal treatment may be limited by unwanted side effects. There is some evidence however from epidemiological research that current use of the combined oral contraceptive pill (OCP) is associated with a reduced incidence of endometriosis. The combined pill has the great advantage over other hormonal treatments that it can be taken indefinitely. The aim of this review was to establish the role of modern oral contraceptives in the management of painful symptoms ascribed to endometriosis. The search strategy of the Menstrual Disorders & Subfertility Group was utilised to identify all randomised trials of the use of oral contraceptives in the treatment of symptomatic endometriosis. In addition a search of the Cochrane Controlled Trials Register was undertaken together with approaches to pharmaceutical companies. An updated search was performed in June 2003 however no new trials were included. All truly randomised controlled trials of the use of oral contraceptive pills in the treatment of women of reproductive age with symptoms ascribed to the diagnosis of endometriosis made visually at a surgical procedure were included. Study quality assessment and data extraction was carried out independently by two reviewers. One of the assessors was an expert in the content matter. Only one study was identified which satisfied the inclusion criteria. The oral contraceptive used in a conventional manner was less effective than a GnRH analogue in the relief of dysmenorrhoea. No significant difference was noted between the effectiveness of the oral contraceptive pill and a GnRH analogue in the relief of dyspareunia or non-menstrual pain. Headaches and weight gain were more commonly associated with oral contraceptive usage than with GnRH analogue usage whereas hot flushes insomnia and vaginal dryness were less common. There is a paucity of data relating to the use of oral contraceptive preparations in the treatment of symptomatic endometriosis. The data such as it is supports the common practice of the use of the oral contraceptive pill as a first line therapy but further research is required to fully evaluate its role in the management of endometriosis. (authors)

The clinical manifestations associated with hyperandrogenism, such as hirsutism and acne, are disturbing to most patients. In addition to correcting androgen-related problems, concerns such as contraception or other metabolic problems (for example, lipid/lipoprotein abnormalities, diabetes, hypertension) associated with these disorders and the effects of unopposed estrogen on the endometrium also need to be considered. Oral contraceptives are a therapeutic modality that may address these multiple problems. The potential mechanisms of action by which oral contraceptives correct excess androgen states include gonadotropin suppression, reduction of circulating androgens, increased androgen binding, suppression of adrenal androgen secretion and inhibition of 5 alpha-reductase, and androgen receptor binding. In normal women, there is good evidence that these actions occur with the use of oral contraceptives. Among women with anovulatory hyperandrogenic states, such as polycystic ovary syndrome, the response to oral contraceptives in each of these areas is somewhat more variable. However, oral contraceptive preparations that are more estrogen dominant appear to produce many of the desired effects. From a clinical standpoint, 60-100% of women with hirsutism improve on oral contraceptives; acne shows improvement in a high percentage of women as well. The use of oral contraceptives also reduces the risk of endometrial hyperplasia that may be associated with anovulatory states. Finally, current low-dose preparations containing the newer progestins (for example, norgestimate and desogestrel) appear to be either neutral, or perhaps beneficial, with respect to their metabolic impact.

In a 2-year longitudinal, calcium-controlled study we evaluated bone density and metabolism in perimenopausal women with initial ovarian failure, and the effects of hormone replacement with a low dose oral contraceptive preparation (OC). In perimenopausal oligomenorrhoic women (n = 16) a significant (P0.01) increase in cycle length and plasma FSH levels as well as a parallel decrease in plasma estradiol levels (P0.01) were evident. In this group, despite the calcium supplementation (500 mg/day), a significant (P0.001) increase in the biochemical markers of bone remodelling paralleled a significant (P0.001) decrease (-3.4% after 24 months) in bone density. Conversely, in premenopausal oligomenorrhoic women treated with a low dose oral contraceptive (OC) formulation (30 mcg ethinyl estradiol plus 75 mcg gestodene, n = 16), bone markers showed a significant (P0.01) decrease, that paralleled a slight but significant (P0.01) increase (+1.71%) in bone density. These data suggest that premenopausal administration of OC can prevent the acceleration of bone turnover and reverse the decrease in bone density that follows the premenopausal impairment of ovarian function.

Desogestrel is a highly selective gonane progestin. A monophasic formulation containing 150 micrograms of desogestrel and 30 micrograms of ethinyl estradiol has recently been approved as an oral contraceptive (OC) in the United States. Although desogestrel-containing formulations are new to the United States, they have been the most widely prescribed OCs in Europe for almost 10 years. An extensive literature demonstrates that desogestrel-containing preparations are safe, effective, and well tolerated by most women. In light of desogestrel's high selectivity, low affinity for androgen receptors, and lack of interference with the increase in sex hormone-binding globulin, desogestrel-containing OCs may be particularly appropriate for women with androgen-induced skin disorders because of their high selectivity. Several European studies have found significant improvement or almost complete resolution of previously existing acne. Desogestrel provides excellent cycle control, no major impact on weight, minimal or no adverse effects on blood pressure, statistically significant increases in high-density lipoprotein cholesterol with low-density lipoprotein cholesterol usually unchanged or reduced, and little effect on glucose tolerance or insulin resistance.

Serum concentration profiles and pharmacokinetic parameters (cmax, tmax, AUC24, AUC0-00, MRT) of ethinylestradiol (EE2) and levonorgestrel (LNG) were obtained following administration of two combined oral contraceptives. The constituents of the preparations were as follows: Gravistat (0.05 mg EE2, 0.125 mg LNG); Minisiston (0.03 mg EE2, 0.125 mg LNG). In 20 of the volunteers blood samples were taken before and up to 36 hours following the intake of a single table. In 11 women the investigation was carried out at day 21 of a treatment cycle (steady-state condition). In spite of pronounced interindividual variations of the pharmacokinetic data, a clear dependency of EE2 concentration curves on the estrogen dose of the respective preparation could be demonstrated. Under the condition of steady-state (21st day of administration) there was a slight but significant rise of the EE2 peak serum concentrations and a pronounced increase of the LNG levels, closely reflected by elevation of the AUC values. SHBG serum concentration was significantly increased by the 10th day of treatment in all subjects receiving Gravistat, whereas the mean value in the Minisiston-group did not remarkably change. Although LNG is known to be bound to SHBG with high affinity, the missing parallelism between LNG- and SHBG-concentrations suggests other (additional?) mechanisms for the elevated LNG-binding capacity in women taking combined EE2-LNG preparations.Serum concentration profiles and pharmacokinetic parameters of ethinyl estradiol (EE2) and levonorgestrel (LNG) were obtained after administration of 2 combined oral contraceptives (OCs). The constituents of the preparations were as follows: Gravistat (0.05 mg EE2, 0.125 mg LNG); Minisiston (0.03 mg EE2, 0.125 mg LNG). Blood samples were taken before and up to 36 hours after intake of a single tablet by 20 volunteers. In 11 women, the investigation was conducted on day 21 of a treatment cycle (steady-state condition). In spite of pronounced interindividual variations of the pharmacokinetic data, a clear dependency of EE2 concentration curves on estrogen dose of the respective preparation could be demonstrated. With the condition of steady-state (21st day of administration), there was a slight but significant rise of EE2 peak serum concentrations and a pronounced increase in LNG levels, closely reflected by the elevation of the area under curve values. Sex hormone binding globulin (SHBG) serum concentration was significantly increased by day 10 of treatment in all those receiving Gravistat, whereas the mean value in the Minisiston group did not change remarkably. Although LNG is known to be bound to SHBG with high affinity, the missing parallelism between LNG and SHBG concentrations suggests other, possibly additional, mechanisms for the elevated LNG-binding capacity in those women taking combined EE2-LNG preparations.

Healthcare providers and consumers want 3 things from a contraceptive. First, the contraceptive must be effective. Second, there should be few or no serious or significant adverse effects. Third, any side effects that may be related to the method are minimal and should be tolerated by the consumer. To address these issues the pharmaceutical industry and the healthcare delivery system has among its strategic aims the reduction in dosage of the hormones (estrogen and progestin) used in combination oral contraceptives. This strategy has been predicated on the hypothesis that it is the dose of estrogen that is related to cardiovascular disease, specifically myocardial infarction, stroke, and venous thromboembolism.1 The reduction in the estrogen dose has allowed us to arrive at the current availability of what is known as “ultra low-dose estrogen” oral contraceptives, products that contain  20 μg ethinyl estradiol in their formulation. This supplement to the American Journal of Obstetrics and Gynecology is designed to present to the clinician and healthcare provider the results of a large multicenter prospective, randomized trial with an ultra low-dose estrogen oral contraceptive. This particular formulation, Alesse (Wyeth-Ayerst Laboratories, St Davids, Pa), contains 20 μg ethinyl estradiol and 100 μg levonorgestrel. An interim data analysis of the efficacy of this oral contraceptive preparation has been published previously.2 The final data from all participants in the clinical trial have been brought together and are presented for the reader in this supplement. The current epidemiologic literature suggests that by reducing the dose of estrogen in oral contraceptive formulations one can reduce the risk of cerebral thrombosis or hemorrhage (stroke) and also reduce the incidence of venous thromboembolism.1,3 These 2 conditions have well-supported evidence of a dose-response relationship with estrogen. It should be pointed out that for both thrombotic and hemorrhagic stroke recent evidence has suggested that cigarette smoking, rather than the use of the oral contraceptive formulations, is a major risk factor.4, 5 This same conclusion has also been reached in relationship to myocardial infarction and oral contraceptive users, among whom smoking appears to be a greater risk factor than does the use of the oral contraceptive preparation.5-7

Three different oral contraceptive preparations were studied before and after a 3 month treatment period with respect to their effects on plasma lipoprotein parameters. A total of 58 healthy women requesting oral contraception were randomly assigned to three groups. Each woman received either monophasic preparations containing ethinylestradiol and desogestrel (M-DG); ethinylestradiol and gestodene (M-GD); or a triphasic preparation of ethinylestradiol and levonorgestrel (T-LN). As has been reported in other studies, the concentrations of total plasma cholesterol and apolipoproteins B and A-IV did not change significantly in any group. HDL cholesterol, triglycerides, apolipoproteins A-I and A-II increased or tended to increase. Despite the effects of the three hormone preparations on these lipoprotein parameters, however, each led to a highly significant decrease in apolipoprotein E plasma levels. Considering the recently reported observations that oral contraceptives increase the hepatic uptake of cholesterol-rich remnants, this decrease in apo-E plasma levels may in women that take oral contraceptives be directly correlated with increased hepatic lipoprotein metabolism.

Carbohydrate metabolism was prospectively studied in 28 women using triphasic oral contraceptives (TOC) for two years. They were tested using a 100-gram oral glucose tolerance test with measurements of plasma glucose and insulin levels during the three-hour test. The women were randomly assigned to either a norethindrone-containing TOC or a levonorgestrel-containing TOC. Both types of drugs contained the estrogen ethinyl estradiol. No significant changes were noted in the norethindrone TOC group. The levonorgestrel TOC two-year test had a significant elevation of the 0.5- and 2-hour plasma glucose values and the fasting insulin value. These data show that the two triphasic oral contraceptive preparations affect carbohydrate metabolism differently.

The effects of three different desogestrel-containing combined oral contraceptive preparations on lipid metabolism were compared with those of two levonorgestrel preparations. The following preparations were studied: (1) monophasic desogestrel (150/30), (2) monophasic desogestrel (150/20, containing 20 micrograms of ethinyl estradiol instead of 30 micrograms of ethinyl estradiol, (3) biphasic desogestrel, (4) monophasic levonorgestrel (150/30), and (5) triphasic levonorgestrel. The effects of these preparations were assessed on high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B, the ratio of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol, and the ratio of apolipoprotein A-I to apolipoprotein B after 3 months of treatment, and the percentage changes with regard to pretreatment were calculated. The monophasic desogestrel (150/30) and biphasic desogestrel preparations induced higher high-density lipoprotein cholesterol and apolipoprotein A-I levels than did their levonorgestrel-containing counterparts. Low-density lipoprotein cholesterol levels were increased in monophasic levonorgestrel and clearly decreased in the lowest ethinyl estradiol-containing monophasic desogestrel (150/20) and biphasic desogestrel preparations. Apolipoprotein B increased in all preparations. The antiatherogenic indexes (ratios of high-density lipoprotein cholesterol to low-density lipoprotein cholesterol and apolipoprotein A-I to apolipoprotein B were higher for monophasic desogestrel (150/30) and biphasic desogestrel than for comparable levonorgestrel-containing preparations. The differences seen between the desogestrel and levonorgestrel preparations can best be explained by the lower intrinsic androgenicity of 3-keto-desogestrel (active metabolite of desogestrel) than that of levonorgestrel.

After treatment with high dose oral contraceptives, alterations in carbohydrate metabolism including decreased glucose tolerance and increased insulin resistance have been described. The purpose of this study was to determine the effects of a monophase oral contraceptive preparation of levonorgestrel 100 mcg and ethinyl estradiol 20 mcg (LNG/EE 100/20) on carbohydrate metabolism. LNG/EE 100/20 was administered orally once daily for 21 days followed by placebo for 7 days. Glucose tolerance was evaluated with the use of a standard 3-hour glucose tolerance test (GTT after administration of a 75-g loading dose of glucose. The GTT was performed dUring the prestudy period between menstrual cycle days 17 and 26. Testing was repeated during the third and sixth treatment cycles between tablet days 15 and 21. Mean changes from baseline values in glucose and insulin were calculated for each collection time. Forty healthy women were enrolled at a single university outpatient center. Data were available for analysis for 15 subjects who had complete data through 6 cycles. Two subjects with abnormally high pretreatment insulin values were excluded from the analysis. Except for a small mean increase in the 30-minute glucose value at cycle 6, there were no statistically significant changes from baseline in glucose or insulin values for the remaining 13 subjects. These changes were not believed to be clinically important because all individual values remained within the normal range. The results of this study show that this preparation of LNG/EE 100/20 has no clinically important effects on carbohydrate metabolism.

In their paper on the prospect of screening potential oral contraceptive users for the thrombogenic variant factor V Leiden Jan P. Vandenbroucke and colleagues conclude that such a strategy would "deny effective contraception to about 5% of White women while preventing only a small number of fatal pulmonary emboli." Their persistent use of the term "oral contraceptives" fails to distinguish clearly between progesterone-only and combined oral contraceptive preparations which have quite different thrombogenic risk profiles. Furthermore the authors imply that oral contraception is the only effective contraception. This is both erroneous and unhelpful. While screening for factor V Leiden might deny 5% of White women the opportunity of using the combined pill it does not necessarily preclude them from using depot or oral progesterone intrauterine devices or barrier methods all of which are effective in appropriate circumstances. The authors comment about the "related strain due to unappealing methods of contraception" reflects personal prejudice not scientific fact. (full text)

Dermatologists prescribe oral antibiotics to female acne patients on a regular basis. There have been reports of oral antibiotic interaction with oral contraceptive preparations, 1-3 but no clinical study has precisely defined the risk for women taking these medications in combination with oral antibiotics. Amid the uncertainty, some dermatologists recommend that their female acne patients use additional birth control measures as a precaution. Our study examines the frequency of pregnancy in female acne patients taking oral antibiotics in conjunction with oral contraceptives compared with published failure rates for women taking birth control pills alone. Materials and Methods. Female acne patients were interviewed by mail questionnaire and by survey in an outpatient dermatology clinic. Patients were questioned about concurrent usage of their antibiotic and oral contraceptive preparations. Pregnancy occurrence and side effects were also investigated. Further inquiries were made concerning the use of additional medications while receiving the pill/antibiotic combination and