Misreporting of contraceptive hormone use in clinical research participants.

OBJECTIVE: Researchers traditionally rely on participant self-report for contraceptive use. We hypothesized that self-reported contraceptive use by clinical research participants may disagree with objectively measured hormonal status. STUDY DESIGN: We enrolled women in Harare, Zimbabwe, aged 18-34, who by self-report had not used hormonal or intrauterine contraception for >30 days, or depot medroxyprogesterone acetate for >10 months, into a study designed to assess biologic changes with contraceptive initiation and use. Blood samples obtained at enrollment and each follow-up visit (N=1630 from 447 participants) were evaluated by mass spectrometry for exogenous hormones. We individually interviewed a subset of participants (n=20) with discrepant self-reported and measured serum hormones to better understand nondisclosure of contraceptive use. RESULTS: Discrepant with self-reported nonuse of hormonal contraception, synthetic progestogens were detectable in 120/447 (27%, 95% confidence interval 23%-31%) enrolled women. Measured exogenous hormones consistent with use of contraceptive pills (n=102), injectables (n=20) and implants (n=3) were detected at enrollment, with 7 women likely using >1 contraceptive. In-depth interviews revealed that participants understood the requirement to be hormone free at enrollment (100%). Most (85%) cited partner noncooperation with condoms/withdrawal and/or pregnancy concerns as major reasons for nondisclosed contraceptive use. All interviewed women (100%) cited access to health care as a primary motivation for study participation. Of participants who accurately reported nonuse of hormonal contraception at enrollment, 41/327 (12.5%) had objective evidence of nonstudy progestin use at follow-up that disagreed with self-reported nonuse. CONCLUSIONS: Women joining contraceptive research studies may misrepresent their use of nonstudy contraceptive hormones at baseline and follow-up. Objective measures of hormone use are needed to ensure that study population exposures are accurately categorized. IMPLICATIONS STATEMENT: Among Zimbabwean women participating in a contraceptive research study, 27% had objective evidence of use of nonstudy contraceptives at enrollment that disagreed with self-report. Studies that rely on self-report to identify contraceptive hormone exposure could suffer from significant misclassification.

Efecto abortive de los anticonceptivos hormonales: una revisión / Abortifacient effect of hormonal contraceptives: a Review

En gran parte de la comunidad científica, así como del ámbito jurídico, al tratar del embrión no nacido, está vigente el criterio según el cual hay que definir el embarazo como el período que comprende sólo desde la implantación hasta el nacimiento natural. Esto lleva consigo otras novedades; por ejemplo, la redefinición de aborto como la eliminación del embrión sólo en ese período, o la extensión de la anticoncepción a cualquier medio que impida la unión entre los gametos como consecuencia de una relación íntima, o también que elimine el producto de la concepción antes de su implantación. De modo que la industria farmacéutica está lanzando al mercado, bajo el nombre de anticonceptivos, productos que actúan también mediante un mecanismo antiimplantatorio. Este hecho tiene grandes repercusiones éticas con relación al respeto del embrión, que obligan a reflexionar acerca de la valoración moral de la prescripción, dispensación y uso de estos medios. Ahora bien, ¿cuáles de los medios contraceptivos actualmente presentes en el mercado incluyen un efecto antiimplantatorio?, ¿qué mecanismos contribuyen a su acción farmacológica y en qué medida lo hacen? Esto es lo que hemos estudiado en este artículo, basándonos en la bibliografía científica disponible. Aunque no ha sido una tarea sencilla, puesto que los resultados aportados por la literatura varían mucho, se ha tratado de ofrecer una conclusión bastante precisa. Básicamente hemos cumplido un doble objetivo: actualizar y completar los estudios -pocos, parciales o lejanos en el tiempo- que tenían este mismo objeto; y ofrecer una valoración ética respecto al respeto de la vida naciente del uso de los anticonceptivos hormonales que pueden tener efecto antiimplantatorio

Most of the scientific community, as well as in a sector of international Law, when referring to the unborn embryo, pregnancy must be defined as the period extending from implantation to natural birth. This implies some novelty, such as the redefinition of abortion as the elimination of the embryo only within this period, and the extension of contraception to any means that impedes the union of the gametes as a consequence of a sexual intercourse, or also that which eliminates the product of conception prior to its implantation. Therefore, the pharmaceutical industry markets, under the name of contraceptives, products that act also by means of an anti-implantation mechanism. This fact has great ethical implications regarding the respect for the embryo which require a reflection on the moral valuation of the prescription, dispensation and use of these means. One may ask: which of the contraceptive means actually present in the market include an anti-implantation effect? What mechanisms contribute to their pharmacological action and in what measure do they do this? This is what we have studied in this article, based on the available scientific bibliography. We have basically fulfilled a double objective: updating and completing the studies -few, partial or distant in time- that had this same subject matter; and offering a moral valuation on the use of hormonal contraceptives that may have an anti-implantation effect, from the point of view of the respect due to the embryonic life

A stability-indicating HPLC method for medroxyprogesterone acetate in bulk drug and injection formulation.

A stability-indicating HPLC assay method has been developed and validated for medroxyprogesterone acetate (MPA) in bulk drug and injectable suspension. An isocratic RP-HPLC was achieved on a Hichrom C(18) column (150 mm x 4.6mm i.d., 5 microm) utilizing a mobile phase of methanol 0.020 M acetate buffer pH 5 (65:35, v/v) and a photodiode array detector at 245 nm. The stress testing of MPA was carried out under acidic and alkaline hydrolysis, and oxidation conditions. MPA was well resolved from its degradation products, a main related substance (megestrol acetate) and two preservatives (methyl paraben and propyl paraben) with the resolution >or=2. The proposed method was validated for selectivity, linearity, accuracy, precision and solution stability. The method was found to be suitable for the quality control of MPA in bulk drug and injections as well as the stability-indicating studies.

Long-acting delivery microspheres of levo-norgestrol-poly(3-hydroxybutyrate): their preparation, characterization and contraceptive tests on mice.

The preparative technology for sustained release drug delivery microspheres of levo-norgestrol-poly(3-hydroxybutyrate) was optimized based on the in-liquid-drying method. The formation of the drug microspheres was confirmed with differential thermal analysis. The appearance, particle size and distribution, residual CHCl3, drug content, drug release characteristics in vitro, stability and anticonceptive effect on mice of the microspheres were all examined. The average particle size was 64 microm with over 90% of the microspheres being in the range of 28.7-85.8 microm. The residual CHCl3 was lower than 0.001%. The drug release behaviour in vitro could be described by the Higuchi equation and the drug release t1/2 was prolonged by 1.8 times, compared with the original drug LNG. The microspheres were stable for 3 months and showed significant sustained release and anticonceptive effect in mice, and lower toxicity compared with the original drug.

Elevated serum prolactin level with high-dose estrogen contraceptive pills.

BACKGROUND AND OBJECTIVES: There are currently groups of women using high-dose estrogen contraceptive pills, especially in the developing countries. The aim of this study was to determine the correlation between the duration of contraceptive pill intake, the dose of steroid contained in the contraceptive pills and the incidence and degree of serum prolactin level elevation in those women. STUDY DESIGN: This study was conducted in 100 contraceptive pill users. Women were randomly selected for this study with an age range from 19 to 35 years and duration of contraceptive pill intake from 6 to 120 months. Cases were classified into two groups. The first group (50 cases) were taking high-dose estrogen pills (50 micrograms) and the second group (50 cases) were taking low-dose estrogen pills (30 micrograms). RESULTS: The results of the present study showed that there was a significant elevation in serum prolactin level in both groups, with a more significant elevation in the high-dose pill users. CONCLUSIONS: There is a positive relationship between serum prolactin level and the duration of pill intake and their steroid content, and this relationship is not related to the age and parity of the women. The groups of women studied are scheduled for follow-up to determine if there is any future drawback which results as a consequence of the developed hyperprolactinemia. Prolactin determination should be considered for all women prior to pill intake. This determination of serum prolactin level prior to pill use will be useful in the evaluation of the future relationship between the estrogen content of the pills and the later development of hyperprolactinemia.

Assay of certain oral contraceptive formulations by gas chromatography-mass spectrometry-selected ion monitoring.

The combined technique of gas chromatography--mass spectrometry--selected ion monitoring (GC-MS-SIM) has been employed for the nanogram level determination of ethinyloestradiol, mestranol, norgestrel and norethisterone in various oral contraceptive formulations. Steroids were assayed as their DMES-or methoxime DMES ether derivatives in the presence of ethisterone as the internal standard. The method is accurate, specific and suitable for single tablet assay.

Dissolution testing of norethindrone:ethinyl estradiol, norethindrone:mestranol, and norethindrone acetate:ethinyl estradiol combination tablets.

Dissolution of oral contraceptive combination products from six manufacturing firms was studied utilizing the rotating basket method at 100 rpm in 600 mL of 0.1 M HCl and 0.02% sodium lauryl sulfate (SLS). Most of the combination products of norethindrone (NE):ethinyl estradiol (EE) dissolved satisfactorily in water using the paddle method which was first proposed by U.S.P., whereas three of 18 tested products showed better dissolution in acidic aqueous medium containing SLS. Acidic medium with surfactant was also found to be suitable for combination products of norethindrone (NE):mestranol (ME) and norethindrone acetate (NEAc):ethinyl estradiol (EE). A modified U.S.P. assay procedure, a reversed-phase high-performance liquid chromatographic (HPLC) method with a mobile phase of acetonitrile and phosphate buffer, was used to analyze NE and EE concurrently. The NEAc and ME were analyzed separately in these combination products. The NEAc was found to hydrolyze to some extent (approximately 20% in 8 h) in acidic dissolution medium at room temperature, but less so at 4 degrees C. The NE was identified as the sole degradation product of NEAc hydrolysis and was also measured to account for the total amount of NEAc dissolved. A simple dissoluting testing method which utilizes a single dissolution medium was applicable for all oral contraceptive combination tablets surveyed.

Automated stability-indicating high-performance liquid chromatographic assay for ethinyl estradiol and (levo)norgestrel tablets.

An automated high-performance liquid chromatography (HPLC) assay for ethinyl estradiol and norgestrel or levonorgestrel in oral contraceptive tablets was developed. Tablets were prepared for on-line injection using a solid sampler and segmented continuous flow techniques. The active components were separated from tablet excipients, impurities, and degradation products on reversed-phase C8 and C18 columns by elution with water-acetonitrile-methanol (45:35:15). A UV detector connected in series with a fluorometric detector measured the UV absorbance of levonorgestrel and norgestrel at 240 nm and the fluorescence of ethinyl estradiol at 310 nm (excitation at 210 nm). The method employed computer control of the injection system and solid sampler for synchronization of the chromatographic and segmented flow streams. The method is applicable for content uniformity and stability testing at a rate of eight samples per hour.

Reversed-phase high-performance liquid chromatography for the determination of steroid hormones in oral contraceptives.

Reversed-phase high-performance liquid chromatography with UV detection is studied for the determination of both progestogenic and oestrogenic components of oral contraceptive formulations. The applicability of the assay is demonstrated for a number of different progestogen-oestrogen combinations in both conventional tablet and novel "paper" formulations. The results show that the method developed is a versatile technique for the routine assay of these pharmaceutical formulations.

[The first three-stage preparation for hormonal contraception. Clinical results (author's transl)]. / Erstes Dreistufenpräparat zur hormonalen Konzeptionsverhütung. Klinische Ergebnisse.

The controlled clinical trial is reported of a new three-stage oral contraceptive which has meanwhile been introduced on to the market under the trade name Triquilar. Triquilar has a reliable contraceptive action: no pregnancy occurred in 8068 treatment cycles. In spite of the very low doses of estrogen and gestagen--Triquilar contains the lowest total quantity of steroids of all available preparations--the multistage structure guarantees an outstanding cycle control and a particularly good general tolerance. The reasons are discussed which today support the use of an oral contraceptive with the lowest possible amounts of the two hormone components.

PIP: A study comparing 2 triphasic hormonal contraceptive preparations (combinations of ethinyl estradiol and levonorgestrel) is reported. SH B 264 AB was used by 594 women for 6628 cycles with no pregnancies, while 634 women used SH B 261 AB for 6025 cycles with 1 pregnancy. A lower incidence of breakthrough bleeding and spotting was observed among SH B 264 AB users, and this preparation ("Triquilon") is preferred to the other. Triquilon users had a menstrual cycle length of 26-30 days and an amenorrhea rate of .4%. There was a low rate of breakthrough bleedings and spottings, which was higher when patients forgot to take their pills. In the vast majority of Triquilar users, body weight and blood pressure remained constant. Subjective side effects (e.g. nausea, dizziness, headache) were infrequent and decreased as the length of Triquilar use increased. A separate study of 1440 cycles of Triquilar use and 1343 cycles of Microgynon use showed that, while the contraceptive effectiveness was the same, the incidence of breakthrough bleeding and spotting was significantly less frequent among Triquilar users.

When patients 'can't' take the pill.

Most side effects of oral contraceptives can be attributed to an excess or a deficiency of estrogen or progestin. Knowledge of the relative amounts of estrogen and progestin in the available preparations permits a rational adjustment of dosage if side effects occur. With this information, nearly every woman who wants to use birth control pills can.

[Simultaneous determination using gas chromatography of mestranol and norethisterone in estrogen-progestins combination for oral use]. / Determinazione simultanea mediante gas-cromatografia del mestranolo e del noretisterone nelle associazioni estrogeno-progestiniche per uso orale.

PIP: The article describes a new method to determine the quantity of mestranol and of norethisterone in a combined oral contraceptive. Gas chromatography was used simultaneously to detect both agents, after they were extracted with ethyl acetate from the total compound of the tablet.^ieng

Hormonal contraception: current perspectives. Part I. An analysis of available agents.

PIP: Currently available forms of hormonal contraceptives with regard to their mechanism of action, effectiveness, and side effects are reviewed. The effectiveness of an oral contraceptive in preventing pregnancy is directly related to its ability to inhibit ovulation. Other effects are less important. The development of synthetic progestational agents made inhibition of ovulation possible without unacceptable side effects. The chemical structures of several estrogens are shown and their relationship to natural estrogen indicated. The chemical structures of synthetic progestational agents and their relationship to progesterone and testosterone are illustrated. Diethylstilbestrol is a nonsteroidal estrogenic compound with a potency of 1/25 of that of ethinyl estradiol. It is used only as a postcoital contraceptive for occasional use. Medroxyprogesterone acetate is a long-lasting injectable contraceptive agent. Available oral contraceptive preparations are listed by brand names, hormone content, and tablet amount. With combination compounds a 28-day routine of therapy has been established. In recently developed compounds the amount of hormone used has been reduced so that side effects are less. The pregnancy rate is less than .1%. The very low-dose preparations have a higher pregnancy rate and an increased incidence of intermenstrual bleeding. The sequential-type oral contraceptive is no longer available. The progestin-only type contains no estrogen, and they are taken continuously. They do not prevent ovulation. Their contraceptive effect is by alterations in cervical mucus and endometrial or tubal physiology. The pregnancy rate is relatively high. No single preparation is considered as suitable for all women. Patients with varicose veins or previous thromboembolic phenomena should not use any oral contraceptive. The combination preparations are most suitable for the majority of women.^ieng

[Optimal composition of the peroral steroid contraceptive agent]. / Jeste k optimálnímu slození perorálního steroidního kontraceptiva

PIP: The effects of exogenous estrogens on the liver are considered to be 1 of the more difficult obstacles in working out an optimal steroid contraceptive, as the liver is 1 of the specific terminal organs for estrogens. The estrogens used in oral steroid contraceptives are ethinyl estradiol (EE) and mestranol (ME). Attempts to overcome the effects of these exogenous estrogens has lead to investigations of the possibilities of gestagens, which have a significant effect on cytoplasmatic receptors in the cells of the terminal tissues. An optimal steroid compound, which maximizes the contraceptive action while minimizing the side effects has been worked out, consisting of daily doses of .03 mg of EE and .15 mg of d-norgestrel. This compound is considered to sufficiently compensate the estrogen effects of its estrogen component through the action of the gestagen component.^ieng

[How to defferentiate monophasic steroid contraceptives?]. / Jak rozlisovat jednofázová steroidní kontraceptiva

PIP: In examining monophasic oral contraceptives, attention is placed on the composition of these preparations. The estrogen and gestagen activity of these preparations should not be considered separately, as the ultimate effect is a result of the combined effect. These preparations are examined in 3 main groups: those with equal estrogen and gestagen activity, those that are predominantly gestagen, and those that are predominantly estrogen. This allows a certain degree of adaptability in regard to individual physiological conditions. The specific Czechoslovak problem is considered to be the insufficient assortment of these different combinations. All of the current world brands of monophasic oral contraceptives are examined and classified as to content.^ieng