Contraceptive Formulations Research Articles

Multi-year fertility reduction in free-roaming feral horses with single-injection immunocontraceptive formulations

Context. Contraception is increasingly used as a management technique to reduce fertility in wildlife populations; however, the feasibility of contraceptive formulations has been limited until recently because they have required multiple treatments to achieve prolonged infertility. Aims. We tested the efficacy and evaluated potential side effects of two contraceptive formulations, a porcine zona pellucida (PZP) formulation, SpayVac® and a gonadotrophin-releasing hormone (GnRH) formulation GonaCon-B™, in a population of free-roaming feral horses (Equus caballus). Both formulations were developed to provide several years of infertility with one injection. Methods. Females were treated in June 2005 with either GonaCon-B (n = 24), SpayVac (n = 20), adjuvant only (n = 22), or received no injection (n = 18). Females were monitored for fertility status year round for 3 years after treatment. Key results. Both contraceptive treatments significantly reduced fertility for 3 years. Fertility rates for GonaCon-B mares were 39%, 42% and 31%, respectively, and 37%, 50% and 44% for SpayVac mares. During the same seasons, 61%, 67% and 76% of control females were fertile. We found no significant effects from contraceptive treatment on the sex ratio of foals, birthing season or foal survival. Conclusions. These results demonstrated that both vaccines are capable of significantly reducing fertility for several years without boosters. Implications. Contraceptive vaccines examined in the present study represent a useful tool for the management of feral horses, because of their being efficacious for 3 years in the absence of booster immunisations.

High-calcium diet reduces blood pressure, blood volume and preserves vasorelaxation in oral contraceptive-treated female rats

Cardiovascular complications are the major clinical challenges among users of synthetic steroids in oral contraceptive (OC) formulations. Interventions that reduce blood volume and improve vasorelaxation have been shown to reduce hypertension and the associated risk factors. The aim of the present study was to investigate the influence of increasing dietary calcium from 0.9 to 3.0% on the development of OC-induced high blood pressure and associated changes in female Sprague-Dawley rats treated with a combination of OC steroids (1 μg ethinyl estradiol and 10 μg norgestrel; p.o.) daily for 10 weeks. Results showed that OC administration led to significant increases in blood pressure, blood volume and cardiac weight. Conversely, OC caused significant reductions in body weight, urinary excretion of water, plasma levels of calcium, 17β-estradiol and progesterone. Increased dietary calcium attenuated the elevation in blood pressure induced by OC and abrogated the associated changes in blood volume, cardiac weight, plasma calcium and urinary excretion of water. The endothelium-dependent relaxation responses to acetylcholine and endothelium-independent relaxation responses to sodium nitroprusside in noradrenaline-precontracted aortic rings were not significantly different among the groups. The results indicate that increased calcium intake abrogated the development of high blood pressure and associated increased blood volume and cardiac weight during OC treatment. The beneficial effect of increased dietary calcium during OC use may be explained by improved diuretic and preserved vasorelaxant responses.

Effects of synthetic gestagens on fish reproduction

Although it is well known that estrogenic steroidal hormones are able to affect the sexual development and reproduction of fish at low concentrations, no data on environmental effects of the class of progestogenic hormones are available yet. Synthetic gestagens (progestins) are a component in oral contraceptives. Upon their use, a fraction of the progestins will be excreted via urine into the aquatic environment. On the basis of their pharmacological action in mammals, it is supposed that fish reproduction is the most sensitive endpoint for the progestin treatment. In order to test this assumption, the effects of two progestins currently marketed in contraceptive formulations, levonorgestrel (LNG) and drospirenone (DRSP), were investigated in adult fathead minnows (Pimephales promelas) following an Organization for Economic Cooperation and Development 21-d fish reproduction screening assay draft protocol with additional end points. Levonorgestrel was tested at measured concentrations of 0.8, 3.3, and 29.6 ng/L, and DRSP at concentrations of 0.66, 6.5, and 70 microg/L. Both tested progestins caused an inhibition of reproduction. For LNG, this occurred at concentrations of >or=0.8 ng/L, no no-observed-effect concentration (NOEC) could be defined. Higher concentrations resulted in masculinization of females with de novo synthesis of nuptial tubercles. Drospirenone treatment, however, affected the reproductive success of fathead minnow at concentrations of 6.5 microg/L and higher with a clear dose-response relationship and a NOEC of 0.66 microg/L, which is above environmentally relevant concentrations.

Acaciaside-B-enriched fraction of Acacia auriculiformis is a prospective spermicide with no mutagenic property

As a part of our continued venture to develop a safe and effective spermicide, we have identified a triterpene glycoside (Acaciaside-B (Ac-B))-enriched fraction (Ac-B-en) isolated from the seeds of Acacia auriculiformis and evaluated its spermicidal potential in vitro. Sperm motility was completely inhibited within 20 s at a minimum effective concentration (MEC) of 120 microg/ml. Tests for sperm viability by dual fluoroprobe staining showed the effect to be spermicidal with an EC(50) of 35.20 microg/ml. A series of investigations including tests for hypo-osmotic swelling, membrane lipid peroxidation, and electron microscopy document that the spermicidal effect of the fraction involves loss of sperm plasma membrane integrity and dissolution of the acrosomal vesicle--the two most important structural components that play diverse roles in physiological functions of sperm including fertilization. The fraction at 10 x MEC exerted no detrimental effects on in vitro growth of Lactobacillus acidophilus, which is considered the major constituent of vaginal microflora that maintains vaginal health. Ames tests performed with different strains of Salmonella typhimurium including TA 97a, 98, 100, and 102, which detect mutagens causing bp substitution or frameshifting at G-C or A-T bp, demonstrate no mutagenic potential of the fraction. Significant spermicidal potential with no possible mutagenic effect and adverse impacts on lactobacilli growth attests to the credential of Ac-B-en as a prospective future spermicide for the development of a safe and effective vaginal contraceptive formulation.

Repeat Pregnancies Among HIV-Infected Women Enrolled in Clinical Trial PACTG1022

We evaluated the rate and potential predictors of repeat pregnancy during 2 years of postpartum follow-up among women enrolled to a clinical trial that compared 2 initial antiretroviral regimens in pregnancy. These women had intensive follow-up during and after pregnancy including extensive contraceptive counseling and were specifically counseled to avoid subsequent pregnancies on study. We hypothesized that occurrence of repeat pregnancies might be predicted by specific demographic and/or clinical characteristics. By identifying these characteristics we hoped to target HIV-infected women most at risk for repeat pregnancy with more focused contraceptive counseling. (excerpt)

Oral contraceptives in migraine

Combined oral contraceptives are a safe and highly effective method of birth control, but they can also raise problems of clinical tolerability and/or safety in migraine patients. It is now commonly accepted that, in migraine with aura, the use of combined oral contraceptives is always contraindicated, and that their intake must also be suspended by patients suffering from migraine without aura if aura symptoms appear. The newest combined oral contraceptive formulations are generally well tolerated in migraine without aura, and the majority of migraine without aura sufferers do not show any problems with their use; nevertheless, the last International Classification of Headache Disorders identifies at least two entities evidently related to the use of combined oral contraceptives: exogenous hormone-induced headache and estrogen-withdrawal headache. As regards the safety, even if both migraine and combined oral contraceptive intake are associated with an increased risk of ischemic stroke, migraine without aura per se is not a contraindication for combined oral contraceptive use. Other risk factors (tobacco use, hypertension, hyperlipidemia, obesity and diabetes) must be carefully considered when prescribing combined oral contraceptives in migraine without aura patients, in particular in women aged over 35 years. Furthermore, the exclusion of a hereditary thrombophilia and of alterations of coagulative parameters should precede any decision of combined oral contraceptive prescription in migraine patients.

Follicular development in a 7-day versus 4-day hormone-free interval with an oral contraceptive containing 20 mcg ethinyl estradiol and 1 mg norethindrone acetate

Background Combined oral contraceptive (COC) formulations with 20 mcg ethinyl estradiol (EE) have a greater incidence of ovarian hormone production and follicular development, which can be managed by shortening the number of hormone-free days per COC cycle. This study evaluates differences in follicular development during a 7-day versus 4-day hormone-free interval in a COC regimen with 20 mcg EE and 1 mg norethindrone acetate. Study Design Forty-one healthy women were randomized in an open-label fashion to this formulation in either a 24/4 or a 21/7 day regimen for three cycles. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and inhibin B were measured daily from Cycle 2, Day 21 to Cycle 3, Day 3 and on Day 7 of Cycle 3. Follicular diameter and Hoogland score were calculated on Cycle 2, Days 21, 24 and 28 and Cycle 3, Days 3 and 7. Results Sixty-six percent of subjects in the 21/7 group and 70% of the subjects in the 24/4 group developed a follicle greater than 10 mm diameter. Ovarian steroid hormone levels, Hoogland scores and bleeding patterns were not statistically significant between the groups. Conclusion In contrast to prior studies, this analysis suggests no difference in follicle development or bleeding patterns among women receiving a 21/7 or 24/4 regimen of a 20-mcg EE/1-mg norethindrone acetate COC.

Hormonal contraception: recent advances and controversies

This Educational Bulletin outlines delivery systems and contraceptive formulations, summarizes advances in emergency contraception and reviews the effects of hormonal contraception on cancer risks, cardiovascular disease, and bone.

Elements of the Menstrual Suppression Debate

In this article I review common arguments and frameworks used by participants in the debate about extended use of combined hormonal contraceptives (CHCs; usually oral contraceptive pills) for menstrual suppression. I examine the way in which menstruation is described and the scope of risks considered. I consider the role of the pharmaceutical industry, personal and clinical experience, and concerns about the contraceptive effectiveness of contraceptive formulations with lower doses. I also address public consequences of the debate, including the possibility of inciting a pill scare, and increasing product awareness and off-label practice.

Oestrogens and Crohn’s disease: the missed link

Observational studies, sometimes, can not provide us with clear answers for very important questions. The answer for a question on whether sex hormones in general, and oestrogen in particular, play some role in inducing and development of Crohn's disease is uncertain. Study design, inclusion criteria, and different formulations of oral contraceptives may partly explain the conflict results of the published reports. But these may be due to the divergent effects of oestrogen, which are based on dose, tissue specificity and cellular environment. This paper is aimed at examining the influence of androgens on the prognosis of Crohn's disease.

Hormonal contraceptive discontinuation patterns according to formulation: investigation of associations in an administrative claims database

Background Hormonal contraceptive use is generally characterized by poor adherence and relatively high discontinuation. This study investigated whether specific hormonal contraceptive formulations and/or delivery systems might be correlated with discontinuation of contraception. Study Design This was a retrospective descriptive analysis within a large administrative claims database. The sample included women aged 15–40 years with a pharmacy benefit and at least one new hormonal contraception prescription during the study period and no prescription in the previous 6 months. Filled contraceptive prescriptions were grouped into several categories of delivery system, dosage, progestin type and monophasic vs. triphasic formulations. In each, a baseline number of women was established who filled a first prescription for a contraceptive formulation in the specified category. Then, the percentage of these women who filled a prescription for a contraceptive in the same category within 3 months' time was determined. Continuation or change rates were compared within each group. Results Oral contraceptives (OCs) were the least likely to be discontinued at 3 months; injectables were the most likely. OC formulations associated with increased risk of discontinuation (odds ratios above 1.3 representing a 5% or higher increased discontinuation) included very-low-dose (20–25 mcg ethinyl estradiol) pills containing norethindrone acetate or norgestimate, as compared to a preparation with the same progestin type but with a higher dose of estrogen. Desogestrel and norethindrone-containing triphasics were more likely to be discontinued than other triphasic progestins. OC formulations with desogestrel and norethindrone/norethindrone acetate were more likely than formulations with other progestins to be discontinued overall. Conclusions This investigation in a sample of nearly 250,000 women suggests possible associations between discontinuation of hormonal contraception and factors such as estrogen dosing, progestin type and changes in dosage during the cycle. Identification of factors correlated with contraceptive discontinuation may inform management and improve adherence.

Novel ethinyl estradiol-beta-cyclodextrin clathrate formulation does not influence the relative bioavailability of ethinyl estradiol or coadministered drospirenone

Background A new combined oral contraceptive formulation has been developed consisting of a beta-cyclodextrin (betadex) clathrate formulation of ethinyl estradiol in combination with drospirenone (EE-betadex clathrate/drsp). In this novel EE-betadex clathrate/drsp preparation, betadex serves as an inert complexing agent to enhance stability and shelf-life. The study was conducted to investigate the relative bioavailability and pharmacokinetic parameters of EE and drsp after oral administration of EE-betadex clathrate/drsp. Methods This was an open-label, randomized, single-dose, three-period, three-treatment, crossover study conducted in 18 healthy postmenopausal women aged 45–75 years. The women received single oral doses of 40 mcg EE/6 mg drsp formulated as EE-betadex clathrate/drsp or EE/drsp (EE as a free steroid) tablets, or as a microcrystalline suspension on three separate occasions. Serum samples were collected for pharmacokinetic analyses. Results The relative bioavailability of EE and drsp after EE-betadex clathrate/drsp tablet administration was comparable with that achieved with the EE/drsp tablet (107% and 101%, respectively). In addition, the inclusion of EE in a betadex clathrate does not affect the pharmacokinetics of either EE or drsp. There were no safety concerns with any of the medications. Conclusion The betadex clathrate formulation of EE, when combined with DRSP, does not affect the pharmacokinetics and relative bioavailability of either EE or drsp.

Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol for contraception and control of menstrual symptoms

Considerable recent interest has focused on new methods of delivery of oral contraceptives that reduce or eliminate the hormone-free interval in order to improve convenience and acceptability, but maintain contraceptive efficacy, minimize side effects and reduce or eliminate the frequency of withdrawal bleeding episodes. Studies in several countries, including the US, have documented that many women would prefer to have no episodes of withdrawal bleeding when using oral contraceptives. This review focuses on a unique oral contraceptive formulation containing levonogestrel 90 μg and ethinyl estradiol 20 μg, approved for use in a continuous dosing regimen designed to eliminate withdrawal bleeding throughout the entire year.

A continuous regimen of levonorgestrel/ethinyl estradiol for contraception and elimination of menstruation

Clinicians and patients desiring amenorrhea for therapeutic or social reasons will find continuous-use 90 microg levonorgestrel/20 microg ethinyl estradiol to be an attractive oral contraceptive dosing option. Although other formulations of oral contraceptives can be dosed in a continuous manner off-label, the convenience of a 28-day dose pack represents a major advance that will likely increase acceptability of the strategy. The availability of FDA-approved continuous-use 90 microg levonorgestrel/20 microg ethinyl estradiol will help mainstream continuous oral contraception in the same way that Preven and Plan B helped legitimize and mainstream emergency contraception. Patients wishing to use continuous 90 microg levonorgestrel/20 microg ethinyl estradiol must recognize and accept that unscheduled breakthrough bleeding is typical during the first four to six cycles of use. Control of cycle-related symptoms may emerge as an off-label indication for use.

Drospirenone/ethinyl estradiol

Drospirenone 3 mg/ethinyl estradiol 20 microg (24/4) is a new unique oral contraceptive formulation that combines in a novel dosing regimen the lowest dosage of ethinyl estradiol commonly used today with drospirenone, an innovative progestin. Drospirenone is a compound closely resembling progesterone, but with the antimineralocorticoid and antiandrogenic properties of a related therapeutic agent, the diuretic, antihypertensive and androgen receptor antagonist, 17alpha-spironolactone. The prolongation of hormonally active pills in the monthly drospirenone/ethinyl estradiol cycle from 21 days to 24 days, followed by 4 days of inactive pills, is an interesting variant of the recently developed extended pill regimens (1). Recent contraceptive research has focused on improving side effect profiles and providing noncontraceptive health and lifestyle advantages. Many of these benefits are now supported with evidence-based medicine (2). Most available oral contraceptives improve cycle regularity, menstrual pain, excessive menstrual flow and acne. However, weight gain, bloating, food cravings, breast tenderness and mood alterations (especially irritability and depression and the complex of affective, behavioral and somatic symptoms of premenstrual syndrome [PMS] and the severe form of PMS, premenstrual dysphoric disorder [PMDD]) are not generally improved with the traditional oral contraceptive formulations (3). Drospirenone/ethinyl estradiol 24/4 is currently the only hormonally based contraceptive regimen with large, randomized, controlled trials demonstrating efficacy for PMDD. It has received U.S. Food and Drug Administration (FDA) indications not only for the prevention of pregnancy but also for PMDD and for moderate acne vulgaris in women who choose oral contraception for birth control (4, 5).

Body weight and oral contraceptives are the most important modulators of serum CRP levels

Background. C‐reactive protein (CRP) levels are modulated by endogenous and exogenous factors independently of inflammation. The present study investigated the impact of oral contraceptives, endogenous oestrogens, age, gender, smoking, body mass index (BMI) and lipid levels on CRP concentrations in a healthy collective. Methods. Highly sensitive CRP, total cholesterol, HDL‐cholesterol and LDL‐cholesterol levels were measured in 850 blood donors (438 M, 412 F); 227 women in this group used oral contraceptive formulations (OC). Additionally, serum samples from 58 women undergoing in vitro fertilization cycles (IVF) were tested for CRP. Results. The 97.5th percentile of CRP levels of the blood donors was 4.91 mg/L in men, 7.52 mg/L in OC non‐users and 11.95 mg/L in OC users. Overweight gives a 2‐fold increase of median CRP levels in men and women. The combination of overweight and OC use in women resulted in 6‐fold median CRP levels. Age, smoking and lipid levels were influencing factors of lower significance. In IVF patients the elevated oestradiol levels had no influence on CRP concentrations in multivariance analysis. Conclusion. The diagnostic and predictive value of CRP levels is most affected by BMI and oral contraceptive use, which suggests the need for further investigations into the role of CRP modulating factors in monitoring infectious diseases.

Ovarian Cancer Protection from Oral Contraceptives Is Greatest with the Lowest Doses of Hormones

Oral contraceptive use has a well-established association with a reduced risk of ovarian cancer; new evidence from a populationbased case-control study suggests that pills with the lowest hormonal content offer the greatest protection. The odds of ovarian cancer were reduced by up to 80% among pill users depending on the oral contraceptive formulation. Furthermore the lower the dose of one particular progestin the lower the risk of ovarian cancer. If all women had used some type of birth control pill an estimated four in 10 malignancies might have been avoided; if all had used low-dose pills that proportion would have been almost three-quarters. Using data from two rapid-response systems researchers identified residents of Hawaii and Los Angeles aged 18 and older in whom ovarian cancer was diagnosed between 1993 and 2005; they obtained information about tumor stage grade and histology from pathology and surgical reports. A control group of women aged 18 and older with no history of ovarian cancer was randomly selected from among respondents to an annual household survey in Hawaii and by random digit dialing in Los Angeles. Participants completed interviews covering demographic socioeconomic health-related and contraceptive information; interviewers used monthly calendars and pictures of various oral contraceptives to help women provide detailed information about their reproductive history and pill use. (excerpt)

A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women

To determine the risk for incident myocardial infarction (MI) in women exposed to modern formulations of oral contraceptives (OCs). Population-based, prospective cohort study begun in 1991 with follow-up through 2002 for an average of 11 years. A total of 48,321 Swedish women aged 30-49 randomly selected from the population residing in the Uppsala Health Care Region of Sweden in 1990-91. Fatal and nonfatal MI ascertained through linkages with nationwide health registries for death, hospitalization, and emigration. There were 214 incident cases of MI. Compared with never users, neither former (relative risk, 1.0; 95% confidence interval, 0.7-1.4) nor current (relative risk, 0.7; 95% confidence interval, 0.4-1.4) OC users at study enrollment had an elevated risk of future MI in models adjusted for coronary heart disease risk factors. Risk of MI was not elevated by prolonged use or in subgroups defined by characteristics of the women or types of OC. Use of OC was not associated with an increased risk of MI in this prospective study, in which most current users of OC were taking low-dose estrogen and second- or third-generation progestins.

Drospirenone: a novel progestin

Drospirenone is a novel progestin available in combined oral contraceptives and menopausal hormonal therapy. Similar to its parent compound spirolactone, an analog of spironolactone, drospirenone has antimineralocorticoid and antiandrogenic activity. Combined with ethinyl estradiol in oral contraceptive formulations, drospirenone-containing contraceptives have similar efficacy and safety profiles to other low-dose oral contraceptives, but seem to offer improved tolerability with regard to weight gain, mood changes, acne and treatment of a severe form of premenstrual syndrome called premenstrual dysphoric disorder. Combined with estradiol as a continuous hormone therapy regimen, the compound was shown to reduce vasomotor symptoms, maintain bone mass, have a beneficial effect on body weight and, more importantly, was shown to lower blood pressure in postmenopausal women.

Is Nonstop Oral Contraception a Desirable Way to Take the Pill

New oral contraceptive (OC) formulations feature shorter hormone-free intervals or continuous use of hormones (Journal Watch Women’s Health Aug 31 2006). In a manufacturer-sponsored, open-label North American trial, investigators assessed the efficacy and safety of a continuous OC formulation combining 20 μg ethinyl estradiol and 90 μg levonorgestrel (similar to Alesse and Levlite). The study OC was supplied in 28-day packs …