Iron-Containing Oral Contraceptives and Their Effect on Hemoglobin and Biomarkers of Iron Status: A Narrative Review.

Oral contraceptive use has been associated with decreased menstrual blood losses; thus, can independently reduce the risk of anemia and iron deficiency in women. Manufacturers have recently started to include supplemental iron in the non-hormonal placebo tablets of some contraceptives. The aims of this narrative review are: (i) to describe the relationship between oral contraceptive use and both anemia and iron status in women; (ii) to describe the current formulations of iron-containing oral contraceptives (ICOC) available on the market; and (iii) to systematically review the existing literature on the effect of ICOC on biomarkers of anemia and iron status in women. We discovered 21 brands of ICOC, most commonly including 25 mg elemental iron as ferrous fumarate, for seven days, per monthly tablet package. Our search identified one randomized trial evaluating the effectiveness of ICOC use compared to two non-ICOC on increasing hemoglobin (Hb) and iron status biomarker concentrations in women; whereafter 12 months of contraception use, there were no significant differences in Hb concentration nor markers of iron status between the groups. ICOC has the potential to be a cost-effective solution to address both family planning needs and iron deficiency anemia. Yet, more rigorous trials evaluating the effectiveness of ICOC on improving markers of anemia and iron deficiency, as well as investigating the safety of its consumption among iron-replete populations, are warranted.

Herbal supplements interactions with oral oestrogen-based contraceptive metabolism and transport.

The increased use of herbal supplements as complementary or alternative medicines has become a clinical conundrum due to the potential for herb-drug interactions. This is exacerbated by an increased supply of new herbal supplements in the market claiming various health advantages. These herbal supplements are available as over-the-counter self-medications. Herbal supplements are generally perceived as efficacious without side effects commonly associated with conventional drugs. However, despite regulations, claims related to their therapeutic effects are mostly unsupported by scientific evidence. These products often lack suitable product quality controls, labelled inadequately and with batch to batch variations, potentially compromising the safety of the consumer. Amongst health practitioners, the greatest concern is related to the lack of chemical characterization of the active compounds of the herbal supplements. The interaction between these different active components and their concomitant effects on other conventional drugs is generally not known. This review will focus on herbal supplements with the potential to effect pharmacokinetic and pharmacodynamic properties of oestrogen-based oral contraceptives. The use of herbal supplements for weight management, depression, and immune boosting benefits were selected as likely herbal supplements to be used concomitantly by women on oral contraceptives.

Effect of six-month use of oral contraceptive pills on plasminogen activator inhibitor-1 & factor VIII among women with polycystic ovary syndrome: An observational pilot study.

Background & objectives: Polycystic ovary syndrome (PCOS) is an endocrinopathy warranting lifelong individualized management by lifestyle and pharmacological agents mainly oral contraceptive pills (OCPs). This study was aimed to report the impact of six-month OCP use on plasminogen activator inhibitor-1 (PAI-1) and factor VIII (FVIII) in women with PCOS. Methods: PCOS women diagnosed on the basis of Rotterdam 2003 criteria, either treated with OCPs (ethinyl estradiol-0.03 mg, levonorgestrel-0.15 mg) for a period of six months (n=40) or drug-naïve (n=42), were enrolled in this study. Blood was drawn to estimate glucose, insulin levels and lipid profile. Chemiluminescence immunoassays were used to measure hormones (LH, FSH, PRL, T4). Plasma levels of PAI-I and FVIII were measured by commercially available kits. Results: Menstrual regularity, Ferriman-Gallwey score and serum total testosterone significantly improved in the OCP group compared to drug-naïve group (P<0.01). No significant difference was observed in PAI-1 levels of the two groups; however, significant decrease in FVIII levels was observed in OCP group as compared to drug-naïve group. PAI-1 levels of OCP group correlated positively with blood glucose two hours, triglycerides and insulin two hours, while FVIII levels of OCP group correlated negatively with fasting insulin and homoeostatic model assessment-insulin resistance. Interpretation & conclusions: OCPs use has differential effect on pro-coagulant markers among women with PCOS. Well-designed, long-term, prospective, large-scale studies are prerequisite to elucidate the efficacy and safety of OCP in the treatment of PCOS.

Effects of oral contraceptives on metabolic profile in women with polycystic ovary syndrome: A meta-analysis comparing products containing cyproterone acetate with third generation progestins.

BACKGROUND: Although oral contraceptives (OCs) are the most common treatment in women with polycystic ovary syndrome (PCOS), their effects and safety on the metabolic profiles of these patients are relatively unknown. In this meta-analysis the effects of the different durations (from 3months to 1year) of OC treatment using cyproterone acetate (CA) or third generation progestins on metabolic profile of patients with PCOS were assessed. MATERIALS AND METHODS: PubMed, Scopus, Google Scholar and ScienceDirect databases (2001-2015) were searched to identify clinical trials investigating the effects of OC containing CA or third generation progestins on metabolic profiles of women with PCOS. Both fixed and random effect models were used. Subgroup analyses were performed based on the progestin compounds used and on duration of treatment. RESULTS: Oral contraceptive (OC) use was found to be associated with a worsening in lipid profiles but no changes were observed in other metabolic outcomes, including body mass index (BMI), fasting blood glucose (FBG), fasting insulin, homeostatic model for measuring insulin resistance (HOMA-IR) and in blood pressure (BP) values. All studied OCs showed similar effects on lipid profiles but with different timings, with products containing CA, requiring 6months to raise high density lipoprotein-cholesterol (HDL-C) levels and 12months to increase triglycerides (TG). On the contrary, products containing drospirenone (DRSP) or desogestrel (DSG) increased HDL-C after only 3months but determined elevations of TG after 6months. All OCs induced an increase in low density lipoprotein-cholesterol (LDL-C) after 12months of use. CONCLUSIONS: The study shows that, in women with PCOS, OC use is associated with significant changes in lipid profiles, including elevation not only in HDL-C but also in TG and LDL-C. All OCs studied showed similar effects but with different timings, with products containing CA generally requiring more prolonged use to increase serum lipids. Instead, OC use does not affect body weight, BP or glucose levels, with only some minor increase of fasting insulin levels.

Modeling the photocatalytic mineralization in water of commercial formulation of estrogens 17-ß estradiol (E2) and nomegestrol acetate in contraceptive pills in a solar powered compound parabolic collector.

Endocrine disruptors in water are contaminants of emerging concern due to the potential risks they pose to the environment and to the aquatic ecosystems. In this study, a solar photocatalytic treatment process in a pilot-scale compound parabolic collector (CPC) was used to remove commercial estradiol formulations (17-ß estradiol and nomegestrol acetate) from water. Photolysis alone degraded up to 50% of estradiol and removed 11% of the total organic carbon (TOC). In contrast, solar photocatalysis degraded up to 57% of estrogens and the TOC removal was 31%, with 0.6 g/L of catalyst load (TiO2 Aeroxide P-25) and 213.6 ppm of TOC as initial concentration of the commercial estradiols formulation. The adsorption of estrogens over the catalyst was insignificant and was modeled by the Langmuir isotherm. The TOC removal via photocatalysis in the photoreactor was modeled considering the reactor fluid-dynamics, the radiation field, the estrogens mass balance, and a modified Langmuir-Hinshelwood rate law, that was expressed in terms of the rate of photon adsorption. The optimum removal of the estrogens and TOC was achieved at a catalyst concentration of 0.4 g/L in 29 mm diameter tubular CPC reactors which approached the optimum catalyst concentration and optical thickness determined from the modeling of the absorption of solar radiation in the CPC, by the six-flux absorption-scattering model (SFM).

Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age.

Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks.

[Oral contraceptive pill and thrombotic risk: epidemiological studies]. / Pillola e rischio trombotico: gli studi wpidemiogici.

The venous thromboembolism (VTE) is a rare event during childbearing age and during the assumption of combined oral contraceptive. The absolute risk of VTE in users of combined oral contraceptives is 20-30 per 100000 women years. A number of case-control studies published in recent years have shown an apparent increase in the risk of VTE among users of oral contraceptives (OCs) containing desogestrel, gestodene, drospirenone and cyproterone, relative to the use of levonorgestrel. The data derived from these recent studies is of borderline statistical significance because any important factors are not considered to evaluate the real correlation between the assumption of OCs and risk of venous thromboembolism. Among the factors that should be considered, there are: EE dose, duration of use, coexistance of other risk factors of venous thromboembolism (age, BMI, familiarity, surgical interventions) and other prescription bias. The lack of these factors is likely to contribute to the increased risk of venous thromboembolism observed in users of third-generation OCs when compared to that in users of second-generation OCs. To date, because of the inadequacy of epidemiological studies, the data about the correlation between OCs and TVE, are not conclusive and it will be necessary to carry out other studies to clarify this debating point, definitively.

A cross-sectional study of different patterns of oral contraceptive use among premenopausal women and circulating IGF-1: implications for disease risk.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is important in normal growth, development, and homeostasis. Current use of oral contraceptives (OC) decreases IGF-1 concentrations; however, the effect of past use, age/timing of use, and type of OC used on IGF-1 levels is unknown. OC are the most commonly used form of birth control worldwide. Both IGF-1 and OC use have been linked to premenopausal breast and colorectal cancers, osteoporosis and cardiovascular disease (CVD). Understanding the effects of different patterns of OC use on IGF-1 levels may offer insight into its influence on disease risk in young women. METHODS: In a cross-sectional study of 328 premenopausal women ages 18 to 21 and 31 to 40 we examined the relationship between different patterns of OC use and circulating IGF-1 using adjusted linear regression analysis. Information on OC use was obtained through an interviewer administered questionnaire. Plasma IGF-1 was assessed with enzyme linked immunosorbent assay (ELISA). RESULTS: Among women aged 18 to 21, ever OC use was significantly associated with decreased IGF-1 levels compared to never use (ß = -57.2 ng/ml, 95% confidence interval (CI): -88.7, -25.8). Among women aged 31 to 40, past users who first used OC at 25 years of age or older (ß = 43.8 ng/ml, 95% CI: 8.8, 78.8), in the last 15 years (ß = 35.1 ng/ml, 95% CI: 9.3, 61.0) or after 1995 (ß = 46.6 ng/ml, 95% CI: 13.4, 79.8) had significantly higher IGF-1 levels compared to never users. CONCLUSION: This is the first study to highlight the long term effects of OC use after cessation on IGF-1 levels among premenopausal women, which previously were thought to be transitory. Future studies of past use and IGF-1 levels are required and must consider age/timing of use and type/generation of OC used. Additional studies are needed to confirm the potential mediation of IGF-1 levels in the links between OC use and health outcomes.

Oral contraceptive use and estrogen/progesterone receptor-negative breast cancer among African American women.

BACKGROUND: Oral contraceptive formulations have changed over time, making it relevant to assess the effect of more recent formulations on breast cancer risk. In addition, some studies have found stronger positive associations of oral contraceptive use with estrogen receptor-negative (ER(-)) than with ER-positive (ER(+)) breast cancer. We carried out the first assessment of the effect of oral contraceptive use on the incidence of breast cancer classified by receptor status among African American women, a group disproportionately affected by ER(-) cancer. METHODS: We followed 53,848 Black Women's Health Study participants from 1995 to 2007 through biennial health questionnaires, in which participants reported information about incident breast cancer, oral contraceptive use, and breast cancer risk factors. Pathology information was obtained on receptor status for 789 incident cases. Incidence rate ratios (IRR) with 95% confidence intervals (95% CI) were derived from Cox regression models with control for confounding factors. RESULTS: Ever use of oral contraceptives was more strongly associated with ER(-)PR(-) breast cancer (279 cases; IRR, 1.65; 95% CI, 1.19-2.30) than with ER(+)PR(+) cancer (386 cases; IRR, 1.11; 95% CI, 0.86-1.42). The risk of ER(-)PR(-) breast cancer increased with increasing duration of use among recent users. CONCLUSIONS: These results indicate that the oral contraceptive formulations used in recent decades increase breast cancer risk in African American women, with a greater effect for ER(-) than ER(+) cancer. IMPACT: Mechanisms to explain the adverse influence of oral contraceptive use on ER(-) breast cancer need to be elucidated.

Danazol-beta-cyclodextrin binary system: a potential application in emergency contraception by the oral route.

This study explored the potential of beta-cyclodextrin to improve the aqueous solubility and dissolution of danazol, investigated a simple and less expensive method for preparation of a danazol-beta-cyclodextrin binary system, and explored the potential application of a danazol-beta-cyclodextrin binary system as a single-dose emergency contraceptive. Phase solubility analysis indicated formation of a first-order soluble complex with stability constant 972.03 M(-1), while Job's plot affirmed 1:1 stoichiometry. The hyperchromic shift in the UV-Vis spectrum of danazol in the presence of beta-cyclodextrin indicated solubilization capability of beta-cyclodextrin for danazol. The extrinsic Cotton effect with a negative peak at 280.7 nm confirmed the inclusion of danazol in the asymmetric locus of beta-cyclodextrin. (1)H-nuclear magnetic resonance analysis suggested that the protons of the steroidal skeleton of danazol display favorable interactions with the beta-cyclodextrin cavity. The danazol-beta-cyclodextrin binary system was prepared by kneading, solution, freeze-drying, and milling methods. The extent of the enhancement of dissolution rate was found to be dependent on the preparation method. Dissolution studies showed a similar relative dissolution rate (2.85) of the danazol-beta-cyclodextrin binary system prepared by the freeze-drying and milling (in the presence of 13% moisture) methods. In a mouse model, the danazol-beta-cyclodextrin binary system at 51.2 mg/kg (equivalent to a 400-mg human dose) showed 100% inhibition of implantation when given postcoitally. Moreover, the danazol-beta-cyclodextrin binary system is safe up to 2000 mg/kg in the mouse (15.52 g/70 kg human) as a single oral dose. Thus, the danazol-beta-cyclodextrin binary system could serve as a new therapeutic application: an oral emergency contraceptive at a physiologically acceptable single dose.

Oral contraceptives and increased headache prevalence: the Head-HUNT Study.

OBJECTIVE: To examine the prevalence of headache and migraine among women using oral contraceptives (OCs) in a large, cross-sectional population-based study. METHODS: In the Nord-Trøndelag Health Study in Norway 1995-1997 (HUNT 2), 27,700 (60%) out of 46,506 invited women responded to headache questions (Head-HUNT). Among 14,353 premenopausal women, 13,944 (97%) responded to questions regarding use of contraceptives. RESULTS: There was a significant association between headache and reported use of estrogen-containing OCs in premenopausal women, both for migraine (OR = 1.4, 95% CI = 1.2 to 1.7) and for non-migrainous headache (OR = 1.2, 95% CI = 1.0 to 1.4). A significant dose relationship between headache and the amount of estrogen in the OCs could not be demonstrated. No significant association between headache and OCs containing only gestagen was found. CONCLUSION: Headache, especially migraine, was more likely among premenopausal women using oral contraceptives containing estrogen.

[Trends of OC use 1980-1999 in a German cohort of women]. / Trend der OC-Nutzung in einer Deutschen Frauen-Kohorte 1980-1999 - Ergebnisse der Deutschen Kohortenstudie zur Frauengesundheit.

INTRODUCTION: There is no doubt, oral contraceptives are a safe, reversible and commonly used method of contraception. Ever use is about 80 % in developed countries and current use of OCs about 40 %. Almost all information about prevalence of OC use came from cross-sectional studies and did not distinguish between high- and low-dose OCs. This paper deals with the prevalence of OC use as it was observed during lifetime of a large cohort of German women by calendar year and estrogen content. METHODS: The prevalence of OC use between 1980 to 1999 was analysed on occasion of an interim analysis of the German cohort study on women's health. This analysis is based on more than 10 000 women with about 390 000 women-years of observation. RESULTS: The proportion of women under the age of 50, that ever used OCs, increased steeply from 1980, i. e. from 62 % (1980) to about 90 % from 1996 onward. The proportion of current users in a given calendar year rose from 44 % (1980) to 49 % (1991-95) and dropped after the "pill crisis 1995". The percentage of current users who used high-estrogen-dose OCs dropped from 32 % (1980) to 5 % (1999). In contrast, the percentage of users of low-dose OCs of the 2nd generation steeply increased as was the percentage of users of the 3rd generation pills, however the latter dropped after 1995. CONCLUSION: The high acceptance of oral contraceptives despite many "pill crises" underlines the continuously high appreciation of their efficacy on the one hand, but underscores also the high responsibility of physicians and industry concerning surveillance or reduction of discussed side effects.

The inhibitory effect of dienogest, a synthetic steroid, on the growth of human endometrial stromal cells in vitro.

Dienogest is a synthetic steroid that has been used as a progestogen in contraceptive pills and is currently being studied for its possible clinical use in the treatment of endometriosis. In this study, we investigated the direct effects of dienogest in differentiation and proliferation of human endometrial stromal cells (ESC) in vitro. After 12 days in the presence of oestradiol (10(-8) mol/l) plus dienogest (10(-6) mol/l), cultured ESC underwent morphological differentiation and produced prolactin, a typical marker for decidualization. By using Northern blot analysis and radioimmunoassay, it was shown that treatment of ESC with oestradiol (10(-8) mol/l) plus dienogest (10(-9) to10(-6) mol/l) led to an increase in the levels of prolactin mRNA and prolactin production in a dose-dependent manner. Additionally, RU-486, a progesterone receptor antagonist, almost completely inhibited dienogest-induced prolactin production. As shown by the thymidine uptake method, there was a dose-dependent inhibition of ESC proliferation with dienogest (P < 0.01, control versus concentrations >10(-7) mol/l). The significant inhibition of ESC proliferation by dienogest (10(-7) mol/l) was partially reversed by RU-486 (10(-6) mol/l). In summary, dienogest directly acts on endometrial tissue in progestogenic response, such as decidualization, increased prolactin production and growth retardation. These data imply that dienogest exerts direct effect in suppressing growth of endometriotic implants.

Sulfamates of various estrogens are prodrugs with increased systemic and reduced hepatic estrogenicity at oral application.

Oral therapy with natural or synthetic estrogens, like ethinylestradiol, suffers from low, suboptimally defined bioavailability and excess hepatic estrogen actions. N,N-alkylated and non-alkylated sulfamates of ethinylestradiol, estradiol and estrone overcome these deficiencies. Ovariectomized Wistar rats (n = 6-7/group) were orally treated for 7 days, and killed on day 8, plasma was gained on days 0, 4, and 8. Systemic estrogenicity was quantified by assessment of uterine weight, vaginal cornification, and measurement of gonadotropins by homologous RIA. Estrogenicity in the liver was analysed. Angiotensinogen was estimated by RIA of angiotensin-1 after incubation of EDTA-plasma with porcine renin. Total and high-density cholesterol were measured by enzymatic methods. Preliminary biotransformation studies were performed after oral administration of 10 micrograms, 5 microCi [2,4,6,7-3H]estradiol sulfamate. Ethinylestradiol led to distinct elevation of angiotensin-1 and dramatic depression of cholesterol fractions, reflecting hepatic estrogen effects, already at doses with marginal systemic effects. Estradiol and estrone had systemic and hepatic estrogenic activity at much higher doses only. Estrogen sulfamates had systemic estrogen activity 10-90-fold above that of their parent estrogen. Non-alkylated sulfamates of given estrogens were more active than N-alkylated ones. Elevation of systemic estrogen activity was always combined with a dramatic reduction of hepatic estrogenicity. Estradiol sulfamate had a 90-fold elevated systemic estrogen activity vs estradiol, but lacked hepatic activity including the 30-fold dose inducing vaginal response. Three hours after administration no unchanged estradiol sulfamate was detectable in plasma. Rather peaks, probably representing estradiol and estrone, were found. Estrogen sulfamates are considered prodrugs of their parent estrogen, which do not interact with any liver function during the first-pass. They represent a new strategy of oral hormone administration. Their main potential seems to be the systemic generation of natural estrogens when used in oral contraceptives.

Norgestimate.

PIP: Norgestimate (NGM) is one of a class of newer, more selective progestins. The authors describe its structure and biologic activity, contraceptive effectiveness, cycle control, metabolic effects, carbohydrate metabolism, coagulation factors, and clinical side effects. NGM-containing oral contraceptives (OC), either as a monophasic or triphasic formulation, perform as well as pills using older progestins. Androgenic side effects, however, are somewhat lower with NGM, but not enough to be of in clinical importance. Clinicians who believe in the potential for clinical consequences associated with changes in lipid and carbohydrate metabolism should make NGM their first choice OC progestin. Although no study has ever demonstrated a long-term superiority of one OC over another with respect to atherogenesis, there is some evidence that changes in HDL and LDL cholesterol, especially over a 20-year period secondary to pill use, may play a role in accelerating or retarding atherosclerosis. There are also multiple influences upon cardiovascular risk, including direct effects of estrogens upon the endothelium. The prudent healthcare professional should therefore choose, with the patient, the preparation which has the most favorable impact upon lipid metabolism.^ieng

Classification and comparison of oral contraceptives containing new generation progestogens.

New generation-oral contraceptives containing desogestrel or gestodene, and possibly also norgestimate, are more or less similar with respect to contraceptive efficacy, cycle control and acceptability. They also show a more favourable metabolic profile in comparison with older preparations. The desogestrel-containing preparations Gracial and Marvelon, and possibly also the gestodene-containing preparation Gynera, have demonstrated a good efficacy in well-controlled studies in the treatment of mild to moderate acne and/or hirsutism. There may be differences between new generation oral contraceptives with respect to their effects on metabolic variables like high-density lipoprotein cholesterol and sex hormone-binding globulin. These differences are most probably modulated by variations in both the pharmacokinetics and selectivity of the progestogenic components. Of particular relevance here may be the recent finding that approximately 20% of administered norgestimate is metabolized into levonorgestrel. For use in clinical practice, it is of considerable help to have different preparations containing a range of oestrogen doses with the same progestogen. They allow the clinician to 'tailor make' the choice of oral contraceptives for those starting pill use or those switching to another combination due to symptomatology or changed circumstances, e.g. advancing age, smoking, etc. In this respect, desogestrel-containing oral contraceptives allow the most flexible approach.

Benefits and risks of oral contraceptive use.

As a general rule, the lowest-dose oral contraceptive should be prescribed that minimizes side effects while maintaining contraceptive protection. A woman who experiences mild side effects should be encouraged to tolerate symptoms for three menstrual cycles before a decision is made to change the prescription. Compliance may also be improved by informing women of the noncontraceptive health benefits of oral contraceptives: less menstrual blood loss and a lower incidence of menorrhagia, irregular bleeding, benign breast disease, endometrial cancer, dysmenorrhea, ovarian cysts or tumors, and salpingitis. Adequate patient education and supportive counseling are key factors in patient satisfaction and hence compliance.

PIP: The effectiveness of monophasic and multiphasic oral contraceptives (OCs) depends on their ability to suppress ovulation, change endometrial growth and ovum receptivity, and reduce cervical mucus receptivity to sperm. They are all more than 99% effective, but, depending on the type and dose of hormone components, they have different side effects. The estrogen component (ethinyl estradiol) of most new OCs is between 30 and 35 mcg, which reduces the risk of estrogen side effects, especially thromboembolism and hypertension. The Food and Drug Administration does not recommend use of an OC with an estrogen component for lactating mothers, while the American College of Obstetrics and Gynecology and the American Academy of Pediatrics believe it is fine. Estrogen may protect against coronary artery disease, yet the estrogen component of today's OCs is so low that the progestin component may cancels this beneficial effect. It also prevents breakthrough bleeding. The most frequently used progestins in OCs are norethindrone and norgestrel. They prevent ovum implantation, sperm penetration through the cervical mucus, and ovulation. Progestins, especially norgestrel, increase the risk of coronary artery disease. Other side effects include acne and weight gain. Progestin benefits are reduced menstrual blood loss, pain during menstruation, premenstrual tension, and endometrial cancer risk. The ideal estrogen-progestin balance depends on the individual, but the estrogen component should be between 30 and 35 mcg, and the progestin component should be the lowest possible dose to reduce metabolic side effects. If an OC user with a well stabilized cycle who takes another recently prescribed drug experiences unexpected breakthrough bleeding or spotting, this change may indicate a drug interaction. Absolute and/or possible contraindications of OC use are smoking after age 35, history of breast or endometrial cancer, liver disease or impaired liver function, cardiovascular risk factors, and diabetes mellitus.

Oral contraception: past, present, and future perspectives.

Oral contraceptives (OCs) were initially approved for unrestricted use in 1960 in the United States and have been used and studied extensively for 30 years. The initial formulations contained a fixed dose of estrogen and progestogen ingested for 21 days, with a seven-day pill-free interval. Subsequent formulations contained a sequential estrogen dose, a progestogen alone given daily, and variable doses of both progestogen and estrogen. Although the estrogen and progestogen doses employed in currently marketed OCs are markedly lower than those used in the OCs of the 1960s and 1970s, the excellent contraceptive efficacy of these compounds has not been compromised. The estrogen component produces a dose-related increase in serum globulin concentrations, triglycerides, and high-density lipoprotein (HDL) cholesterol, along with a decrease in low-density lipoprotein (LDL) cholesterol, while the progestogen component causes peripheral insulin resistance, a decrease in HDL cholesterol, an increase in LDL cholesterol, and various androgenic effects. The effect of nicotine on thromboxane release acts synergistically with the elevated serum clotting factors to increase the incidence of both arterial and venous thrombotic events, particularly in women smokers over 35 years of age. However, there is no evidence of increased risk of myocardial infarction or stroke in healthy, nonsmoking women of any age who use OCs containing less than 50 micrograms estrogen. Likewise, the lower-dose estrogen/progestogen formulations do not have a clinically significant effect on glucose metabolism and have a neutral effect on lipoprotein metabolism. In addition, the many noncontraceptive health benefits associated with OCs are maintained with the lower-dose formulations. Thus, the low-dose formulations should improve the overall health of healthy, nonsmoking women as well as effectively prevent unwanted pregnancy.