Contraceptive Combination Research Articles

Primary prevention of neural-tube defects and some other congenital abnormalities by folic acid and multivitamins: history, missed opportunity and tasks.

The history of intervention trials of periconception folic acid with multivitamin and folic acid supplementation in women has shown a recent breakthrough in the primary prevention of structural birth defects, namely neural-tube defects and some other congenital abnormalities. Recently, some studies have demonstrated the efficacy of this new method in reducing congenital abnormalities with specific origin; for example, in the offspring of diabetic and epileptic mothers, and in pregnancy with high fever. The benefits and drawbacks of four possible uses of periconception folate/folic acid and multivitamin supplementation are discussed: we believe there has been a missed opportunity to implement this preventive approach in medical practice. The four methods are as follows: (i) dietary intake of folate and other vitamins, (ii) periconception folic acid/multivitamin supplementation, (iii) food fortification with folic acid, and (iv) the combination of oral contraceptives with 6S-5-methytetrahydrofolate ('folate').

Variations of the enzyme inducing effects of contraceptive agents in different animal species.

The effects of some of the most frequently used combinations of steroid contraceptives on the liver microsomal enzyme activity were compared in rats mice and guinea pigs. Results of the antifertility activity of the combinations lynestrenol with mestranol norethynodrel with mestranol and norethindrone with mestranol are also reported. With an acute or chronic treatment regimen a range of doses was used to assess a dose-response relationship. Ratios of progestogen to estrogen were used to compare with ratios used for humans. All animals received drug combinations orally daily for 4 or 30 days. Animals used for examination of the liver microsomal enzyme activity were killed at 2 or 18 hours after the last treatment. Rats needed a high dose of each of the 3 combinations to avoid implantations. Mice needed similar doses of lynestrenol with mestranol and of norethindrone with mestranol. However in mice small amounts of norethynodrel with mestranol were still effective. Guinea pigs required lower doses. The activity of liver microsomal enzymes was not changed 2 hours after the last dose of the 4- or 30-day regimen in any species. In rats and mice liver microsomal enzyme activity measured 18 hours after the last dose was increased except norethynodrel with mestranol in mice; liver microsomal enzyme activity was not modified in the guinea pigs. No effect on liver microsomal protein or on the cytochrome P450 concentration was observed in any experiment. Results show a different reactivity in the 3 animal species. The contraceptives were compared only in terms of antifertility activity. The doses used were relatively low for rats and mice but high for guinea pigs. The dose capable of exerting antifertility acitivity and the dose effective in increasing liver microsomal metabolism were not correlated.

Comparative effects of (+)-propranolol and nonoxynol-9 on human sperm motility in-vitro

Using the modified transmembrane migration method to measure sperm motility, it was shown that the surfactant nonoxynol-9 alone, was twice as potent as (+)-propranolol alone as a spermicidal agent. Addition of (+)-propranolol to nonoxynol-9 shifted the dose-response curve to the left of the curves for either component alone, and a surprising synergistic action was evident. These observations may form the basis for the development of a new advantageous topical contraceptive combination product.

The interaction of some oral contraceptive steroids with lipid monolayers and with Erythrocytes.

Abstract Some steroids used in oral contraceptive combinations have been found to interact with cholesterol and lecithin spread as monolayers on water and to protect erythrocytes against haemolysis. No simple relation between steroid structure and these interactions was found, although in general the more water-soluble members of a group of structurally related compounds interacted to a lesser extent. No distinction could be observed in the behaviour of progestogens and oestrogens in the systems studied. It is suggested in the light of the evidence presented here and from data in the literature that these steroids may adsorb at lipid surfaces and may penetrate lipid membranes. This gives substance to the hypothesis that some steroids adsorb at platelet surfaces and alter the surface properties or the permeability of the platelet membrane sufficiently to cause increased platelet aggregation.

Cyproterone acetate or drospirenone containing combined oral contraceptives plus spironolactone or cyproterone acetate for hirsutism: Randomized comparison of three regimens

Objective: To compare the effectiveness of three different combinations of combined oral contraceptives (COCs) and anti-androgens in the treatment of hirsutism. Methods: A total of 134 women with moderate and severe hirsutism were randomly assigned to three treatment regimens: Group I received 30 μg of ethinyl estradiol (EE)/3 mg of drospirenone (DRSP) plus 100 mg of cyproterone acetate (CPA) (n = 45); group II received 30 μg of EE/3 mg of DRSP plus 100 mg of spironolactone (n = 44); and group III received 35 μg of EE/2 mg of CPA plus 100 mg of CPA (n = 45), daily for 6 months. The decrease in the modified Ferriman–Gallwey hirsutism score (mFGS) was the main outcome measure. Results: The mean decrease in mFGS after 3 and 6 months of the treatment course was 26% and 49% in group I (both p < 0.01), 27% and 49% in group II (both p < 0.01), and 25% and 45% in group III (both p < 0.01), respectively, when compared with baseline. Although the mFGS was significantly decreased in all groups, there was no significant difference between groups. Conclusion: CPA or DRSP containing COCs in combination with CPA or spironolactone have similar effects for the treatment of hirsutism.

Weight change and hormonal contraception: fact and fiction

Weight gain is commonly cited as a side effect of hormonal contraception, and may lead to discontinuation or reluctance to initiate. This view is widely held among clients and providers. Combination contraceptives are not associated with weight gain, although among users of depot-medroxyprogesterone acetate weight gain may occur, which may be limited to adolescent users who are overweight or obese at initiation of depot-medroxyprogesterone acetate. Users who rapidly gain weight initially may also be at higher risk of greater weight increase. There is limited information on other progestin-only methods. Women who request contraceptive methods need reassurance and advice from providers to allay their fears of weight gain. The providers, in turn, need to be aware of the available evidence.

Multiple Method Contraception Use among African American Adolescents in Four US Cities

We report on African American adolescents' (N = 850; M age = 15.4) contraceptive practices and type of contraception utilized during their last sexual encounter. Respondents completed measures of demographics, contraceptive use, sexual partner type, and ability to select “safe” sexual partners. 40% endorsed use of dual or multiple contraceptive methods; a total of 35 different contraceptive combinations were reported. Perceived ability to select “safe” partners was associated with not using contraception (OR = 1.25), using less effective contraceptive methods (OR = 1.23), or hormonal birth control (OR = 1.50). Female gender predicted hormonal birth control use (OR = 2.33), use of less effective contraceptive methods (e.g., withdrawal; OR = 2.47), and using no contraception (OR = 2.37). Respondents' age and partner type did not predict contraception use. Adolescents used contraceptive methods with limited ability to prevent both unintended pregnancies and STD/HIV. Adolescents who believed their partners posed low risk were more likely to use contraceptive practices other than condoms or no contraception. Reproductive health practitioners are encouraged to help youth negotiate contraceptive use with partners, regardless of the partner's perceived riskiness.

The future of women's contraception: stakes and modalities

The two main contraceptive methods are the combined pill and the intrauterine device. In several countries, sterilization is a commonly used alternative. The current goals of contraception remain to achieve effective, accessible, reversible, and well-tolerated birth control for everyone. Despite progress, these goals have not been reached. To achieve these goals, it is mandatory to create new hormonal combinations and to discover new contraceptive targets. Recent innovations associate the development of new progestogens, selective progesterone receptor modulators, and the creation of new contraceptive combinations. Other innovations involve the use of natural estrogens but also optimizing existing treatment regimens and doses, as well as the development of new methods of emergency contraception. Finally, a major step will be to invent an efficient contraceptive that carries the lowest possible risk associated with methods protecting against sexually transmitted diseases. In the future, in relation to progress in the fields of genomics, proteomics, and immunology, new methods of contraception will be developed. These methods will be more targeted and will eventually be nonhormonal and independent of sexual activity.

Metformin, naltrexone, or the combination of prednisolone and antiandrogenic oral contraceptives as first-line therapy in hyperinsulinemic women with polycystic ovary syndrome

To compare the short-term effects of metformin (M), naltrexone (N), and a combination of OC and prednisolone (OC/Pr) on the metabolic state and the ovarian function of PCOS women, we randomized 29 women to a 3-month course of therapy. We observed significant improvements in hyperandrogenemia and ovulation rates in PCOS women of all three groups, in the absence of changes in the metabolic state, suggesting that insulin resistance in PCOS patients is only one of several factors leading to hyperandrogenemic ovarian failure.

Bleeding patterns and menstrual-related symptoms with the continuous use of a contraceptive combination of ethinylestradiol and drospirenone: a randomized study

Background The objective of this study was to compare bleeding patterns of women using a contraceptive combination of 30 mcg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) continuously or cyclically. Menstrual-related symptoms were also evaluated. Study Design This open, prospective, randomized study evaluated 78 women using the EE/DRSP combination continuously for 168 days or for six 28-day cycles, each followed by a 7-day hormone-free interval. A diary with pre-established scales was used to assess the frequency and intensity of bleeding and menstrual-related symptoms. Results Amenorrhea increased with continuous use; 62.2% of women with continuous use were amenorrheic at the end of treatment (95% CI: 46.6–77.8%). Dysmenorrhea, headache, acne, nausea, edema and increased appetite improved significantly in the continuous-use group, and mastalgia and edema in the cyclic-use group (p<.05). Six subjects in the continuous-use group (15.4%) and three in the cyclic-use group (7.7%) discontinued due to adverse events. Conclusions Continuous use was associated with amenorrhea and fewer menstrual-related symptoms compared to cyclic use.

Effect of a continuous regimen of contraceptive combination of ethinylestradiol and drospirenone on lipid, carbohydrate and coagulation profiles

Background The objective of this study was to evaluate the effects of a contraceptive pill containing ethinylestradiol (30 mcg) and drospirenone (3 mg) in a continuous regimen on lipid, carbohydrate and coagulation parameters. Study Design This open, prospective, randomized study included 78 participants (mean age 27.8 years) who were randomized into two groups to use the pill continuously for 168 days or for six 28-day cycles with a 7-day hormone-free interval between cycles. Markers of lipid, carbohydrate and coagulation profiles were measured prior to initiation and after the 6 months of pill use. Results No statistically significant differences were found between the two contraceptive regimens with respect to carbohydrate or lipid profiles or in the parameters related to coagulation. Conclusions The contraceptive combination of ethinylestradiol and drospirenone used in a continuous regimen was associated with metabolic alterations similar to those found during the traditional cyclic regimen of oral contraceptive use.

ST Elevation Myocardial Infarction in Young Adult Females

The author questions whether myocardial infarction (MI) in youg adult females less than 35 years of age id due to the increased prevalence of atherosclerotic heart disease in the younger population and suggests that the most likely culprit causing thrombosis in the right coronary artery in this patient could be a combination of smoking and hormonal contraception.

Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers

Risk of venous thrombosis is increased after long-distance travel. Identifying high-risk groups may provide a basis for targeted prevention. We assessed the effect of increased levels of coagulation factors and combinations of risk factors in travelers in a large case-control study. We calculated odds ratios (ORs) for 334 travelers (200 cases and 134 controls) with coagulation factors II (prothrombin), VII, VIII, and IX; fibrinogen, and von Willebrand factor (VWF) above the 80th percentile; for increasing numbers of risk factors; and for specific combinations. The risk was increased in travelers with high FII (OR, 2.2: 95% CI, 1.3-3.7) and FVIII (OR, 6.2, (95% CI, 3.6-10.5) compared with travelers with normal levels. High FIX and fibrinogen levels increased the risk in air travelers (FIX: OR, 3.2; 95% CI, 0.9-11.0; fibrinogen: OR, 2.0; 95% CI, 0.7-5.5) but not in other travelers. The ORs increased with the number of risk factors, and the risk was increased most in women with the combination of oral contraceptives and high FVIII (OR, 51.7; 95% CI, 5.4-498). We conclude that increased levels of FII and FVIII increase the risk of venous thrombosis in travelers. Furthermore, the risk is greatly increased if other risk factors are present as well.

Impact of combined and progestogen-only contraceptives on bone mineral density

Sex steroids are major determinants of bone mass, and hormonal contraceptives may affect bone mineral density (BMD) in women. Combination contraceptives probably have no impact on BMD, except perhaps when started within 3 years after the menarche. Progestogen-only contraceptives are being increasingly used. Injectable medroxyprogesterone acetate, a potent inhibitor of gonadotropin release, can induce bone loss, most notably in young women. Other progestogens are used in lower doses that have weaker antigonadotropin effects. Levonorgestrel and etonorgestrel implants have unclear effects on BMD but are probably safe. The impact of high- and low-dose oral progestogens on BMD has not been investigated, although no adverse effects would be expected.

How effective are pharmacologic treatments for women with hirsutism?

Hirsutism is a common problem that can have profound implications for quality of life and psychological wellbeing. Various nonpharmacologic and pharmacologic strategies are available to manage excess hair. In this Practice Point commentary, I discuss the results of a systematic review, which assessed the relative efficacy of several commonly used pharmacologic agents for the treatment of hirsutism. Koulouri and Conway identified 28 randomized controlled trials of 6 months' duration that assessed four interventions: modulators of metabolism, oral contraceptive pills, antiandrogens, and combination therapy. All treatment options significantly improved the main outcome measure (Ferriman–Gallwey score). Obesity was found to negatively affect treatment efficacy, suggesting that lifestyle modification could represent an important component of the treatment strategy. The study design had several weaknesses, such as the relatively small number of women in each treatment group. Nonetheless, the results add to the evidence base supporting the use of these agents in the treatment of hirsutism.

Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression

Hormone-based contraceptives affect mood in healthy women or in women with premenstrual dysphoric disorder (PMDD). No study has yet examined their association with mood in women with major depressive disorder (MDD). The purpose of this study was to determine whether estrogen-progestin combination or progestin-only contraceptives are associated with depression severity, function and quality of life, or general medical or psychiatric comorbidity in women with MDD. This analysis focused on a large population of female outpatients less than 40 years of age with non-psychotic MDD who were treated in 18 primary and 23 psychiatric care settings across the US, using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Baseline demographic and clinical information was gathered and compared between three groups based on hormonal use: combination (estrogen-progestin)(N=232), progestin-only (N=58), and no hormone treatment (N=948). Caucasians were significantly more likely to use combined hormone contraception. Women on progestin-only had significantly more general medical comorbidities; greater hypersomnia, weight gain and gastrointestinal symptoms; and worse physical functioning than women in either of the other groups. Those on combined hormone contraception were significantly less depressed than those with no hormone treatment by the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated. The combined hormone group also demonstrated better physical functioning and less obsessive-compulsive disorder (COCD) comorbidity than either of the other groups. Synthetic estrogen and progestins may influence depressive and physical symptoms in depressed women.

Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer

There is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT. We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.

Labeling of drugs that interact with oral contraceptives

Background Labeling should clearly describe drug-drug interactions (DDI) between oral contraceptives (OCs) and other drugs. The purpose of this study was to survey the labels of drugs that interact with OCs. Methods Drugs known or suspected to interact with OCs were identified using DRUGDEX®. The following keywords were used: combination contraceptives, levonorgestrel, and norethindrone. Additional drugs were identified from a literature search. Labels were obtained from the Physicians' Desk Reference. Results Our search identified 61 drugs. Twenty-six labels (43%) contained general language about DDI of OCs and 35 (57%) specified interaction with estrogen/progestin components of OCs. Four labels described increased OC exposure but only 1 of these 4 labels recommended a dose reduction of OC. Two labels contained no recommendation about OC dose adjustment while 1 label recommended considering an increase in OC exposure when OCs are prescribed. Of 21 labels describing decrease in OC exposure, 16 recommended additional/different forms of contraception while 8 did not specify any dose adjustment. Four labels recommended a general precaution. Two labels reported unknown clinical significance of decreased OC exposure. Three labels reported a lack of DDI with OCs by evaluating the inhibition of ovulation. Conclusions Label recommendations for OCs regarding DDI vary considerably. DDI between a drug and a specific OC may not apply to all OCs because of different progestins in OCs. Clinical Pharmacology & Therapeutics (2005) 77, P13–P13; doi: 10.1016/j.clpt.2004.11.051

Novel Male Hormonal Contraceptive Combinations: The Hormonal and Spermatogenic Effects of Testosterone and Levonorgestrel Combined with a 5α-Reductase Inhibitor or Gonadotropin-Releasing Hormone Antagonist

We postulated that the addition of a combined types I and II, 5alpha-reductase inhibitor (dutasteride) or long-acting GnRH antagonist (acyline) to combination testosterone plus levonorgestrel treatment may be advantageous in the suppression of spermatogenesis for male contraception. This study aimed to examine effects of novel combination contraceptive regimens on serum gonadotropins and androgens and sperm concentration.This study was divided into three phases: screening (2 wk), treatment (8 wk), and recovery (4 wk). Twenty-two men (n = 5-6/group) received 8 wk of treatment with testosterone enanthate (TE, 100 mg im weekly) combined with one of the following: 1) levonorgestrel (LNG) 125 mug orally daily; 2) LNG 125 microg plus dutasteride 0.5 mg orally daily; 3) acyline 300 microg/kg sc every 2 wk (as a comparator for any additional progestin effects); or 4) LNG 125 microg orally daily plus acyline 300 microg/kg sc every 2 wk. Serum gonadotropin levels were similarly suppressed by all treatments, falling to a nadir between 1.2 and 3.4% and 0.5 and 0.8% baseline for FSH and LH, respectively (P < 0.05). Serum dihydrotestosterone levels were significantly (P < 0.05) decreased in the dutasteride group throughout the treatment period to a nadir of 31% baseline (wk 7). No significant differences in sperm concentrations among treatment groups were seen. Severe oligospermia (0.1-3 million/ml) or azoospermia was seen in none of five and four of five in TE + LNG; two of six and four of six in TE + LNG + dutasteride; two of six and four of six in TE + acyline; and one of five and three of five in TE + LNG + acyline groups, respectively. There was one nonresponder in each of the TE + LNG and TE + LNG + acyline groups.We conclude that the addition of a combined types I and II, 5alpha-reductase inhibitor or long-acting GnRH antagonist to a testosterone plus LNG regimen provides no additional suppression of gonadotropins or sperm concentration over an 8-wk treatment period. However, further evaluation of the effects of these regimens on the testis (including testicular steroid levels and germ cell maturation) and the treatment of larger numbers of men (and for longer periods) may provide data to support their place in contraceptive development.

Clinical and metabolic aspects of the continuous use of a contraceptive association of ethinyl estradiol (30 μg) and gestodene (75 μg)

This open, prospective, noncomparative study evaluated clinical and metabolic aspects of the use of a contraceptive combination of ethinyl estradiol (30 μg) and gestodene (75 μg) continuously for 24 weeks in 45 women aged 25±3.7 years. No alterations in weight or blood pressure were observed. Few side effects were recorded. Amenorrhea rates increased from the fourth month of observation onwards, reaching 81.2% by week 24. A reduction in the levels of cholesterol and LDL and an increase in HDL and triglycerides were observed. Insulin levels increased but not significantly, while levels of glycemia remained unchanged. Levels of antithrombin III, fibrinogen and plasminogen activator inhibitor-1 (PAI-1) increased, whereas a reduction was observed in proteins C and S and in prothrombin time (PT). Activated partial thromboplastin time (APTT) remained unchanged. The treatment was associated with satisfactory clinical effects, high rates of amenorrhea after the third treatment cycle, and resulted in metabolic changes similar to those encountered during the classic use of contraceptive pills with monthly interruption for withdrawal bleeding.