Factors affecting the enterohepatic circulation of oral contraceptive steroids

Oral contraceptive steroids may undergo enterohepatic circulation, but it is relevant for only estrogens, because these compounds can be directly conjugated in the liver. Animal studies show convincing evidence of the importance of the enterohepatic circulation, but studies in humans are much less convincing. The importance of the route and the rate of metabolism of ethinyl estradiol are reviewed. Some antibiotics have been reported anecdotally to reduce the efficacy of oral contraceptive steroids, but controlled stuides have not confirmed this observation. Although gut flora are altered by oral antibotics, the blood levels of ethinyl estradiol are not reduced, and one antibiotic at least (cotrimoxazole) enhances the activity of ethinyl estradiol.     

Pharmacokinetics and pharmacodynamics of oral contraceptive steroids: Factors influencing steroid metabolism

The time-dependent alterations in the serum concentrations of ethinyl estradiol, gestodene, and 3-keto-desogestrel during treatment with 30 µg of ethinyl estradiol + 75 µg of gestodene or 30 µg of ethinyl estradiol + 150 µg of desogestrel were investigated during 12 months. The levels of gestodene and 3-keto-desogestrel increased between days 1 and 21 of each cycle, reaching maximal levels during the third and sixth cycles. The serum concentrations of gestodene were fourfold to fivefold higher than those of 3-keto-desogestrel. The ethinyl estradiol levels increased significantly between days 1 and 10 during each cycle and were significantly higher by 70% during intake of ethinyl estradiollgestodene compared with ethinyl estradiolldesogestrel, although the dose was identical. Intake of gestodene, in addition to 35 µg of ethinyl estradiol + 2 mg of cyproterone acetate, caused a rise in ethinyl estradiol levels. During treatment with ethinyl estradiollgestodene and an additional 150 µg of levonorgestrel, there was a continuous increase in gestodene levels, although sex hormone-binding globulin level did not change. During treatment with 30 or 35 µg of ethinyl estradiol and 75 µg of gestodene, 150 µg of desogestrel, or 2 mg of cyproterone acetate, there were large intraindividual and interindividual variations in the steroid levels and ratios of estrogen: progestogen levels. There was no correlation with the occurrence of intermenstrual bleedings. It is concluded that ethinyl estradiol and nortestosterone derivatives may inhibit steroid-metabolizing enzymes in the liver, which results in a rise in the serum levels of contraceptive steroids. The cause of the large intraindividual variations is as yet unknown, but it is probably from changes in steroid metabolism.     

Gastrointestinal disease and oral contraception

Oral contraceptive steroids play a major role in modern family planning. With the present tendency to decrease the doses of both estrogens and progestogens, any factor that reduces the bioavailabilty of the lower-dose preparations may have an impact on contraceptive protection. Although ethinyl estradiol, the most commonly used oral estrogen, is liable to an enterohepatic circulation as unchanged drug, the commonly used progestogens are not. At present, no convincing evidence exists in the human subject that disruption of the enterohepatic circulation by antibiotics or antacids does reduce contraceptive efficacy of the pill. Oral contraceptive steroids are mainly absorbed from the small bowel, and contraceptive efficacy depends on its absorptive capacity. Enhanced passage of gastrointestinal contents or impaired absorption may thus contribute to contraceptive failures in patients who have chronic inflammatory disease, diarrhea, ileostomy, or jejunoileal bypass.     

Binding of oral contraceptive progestogens to serum proteins and cytoplasmic receptor

Some progestogens widely used in oral contraceptives are characterized at the level of high-affinity receptor binding as well as binding to sex hormone-binding globulin and corticosteroid-binding globulin. With regard to binding to sex hormone-binding globulin, gestodene, levonorgestrel, and to a lesser extent 3-ketodesogestrel (which is only formed from the prodrug desogestrel in the body), show a behavior that is manifested in the relatively high affinity to sex hormone-binding globulin, whereas desogestrel and norgestimate do not display any measurable affinity for this specific steroid-binding serum protein. Furthermore, levonorgestrel and gestodene dissociate very much more slowly from the binding sites of sex hormone-binding globulin than 3-ketodesogestrel. A natural affinity of all these synthetic progestogens tested for corticosteroid-binding globulin could not be established. Gestodene, levonorgestrel, and 3-ketodesogestrel bind to the progesterone, glucocorticoid, and androgen receptor with high affinity, apart from slight differences, whereas estrogen receptor affinity could not be demonstrated in any of the progestogens investigated. In relation to aldosterone, the relative binding affinity values of gestodene, levonorgestrel, and the natural progestogen progesterone are relatively high, whereas 3-ketodesogestrel does not display any measurable affinity for this receptor species.     

Treatment of hirsutism with combined pill containing drospirenone

The aim of the present study was to evaluate the biochemical and clinical effects of the combined pill consisting of ethinyl estradiol (EE) and drospirenone (DRSP) in hirsute patients. Fifty-two adolescents or young women from Greece were treated with 30 μg EE and 3 mg DRSP for 1 year. Hirsutism was evaluated by the Ferriman–Gallway (FG) score in the initial visit and at 3, 6 and 12 months. Follicle-stimulating hormone, luteinizing hormone, etradiol, free and total testosterone (T), sex hormone-binding globulin (SHBG), androstenedione and dehydroepiandrosterone sulfate were determined at the same intervals. Hirsutism improved and FG scores reduced to 77.4%, 67.2% and 51.8% at 3, 6 and 12 months, respectively. Plasma SHBG levels rose, while free and total T levels reduced from the third month onwards. In conclusion, the EE/DRSP pill improves hirsutism in women via antiandrogenic and antimineralocorticoid action. The biochemical manifestations of hyperandrogenism are also improved.     

Effects of contraceptive steroids on carbohydrate and lipid metabolism

The available types and modes of actions of oral contraceptives precede a review of theories on how oral contraceptives cause impaired glucose tolerance and lipid anomalies. It was long considered proven that only the estrogens in the pill decreased glucose tolerance, but nonsteroids, with the exception of lynestrenol and norethisterone, also harm glucose tolerance in a dose-related manner when combined with synthetic estrogens. Some of the proposed mechanisms include: direct stimulation of insulin secretion, increase in insulin/glucagon ratio in response to arginine, increased secretion of somatotropin, decreased catabolism of cortisol, deficiency of Vitamin-B6, and excess gluconeogenesis. Synthetic estrogens stimulate, while progestagens antagonize, elaboration of triglycerides and cholesterol in plasma. Both the pill and the diabetic disease process increase blood clotting by augmenting platelet aggregation and blood clotting factors. The ideal oral contraceptive for diabetics is probably the progestagen-only pill or a minipill.     

The use of an oral contraceptive containing estradiol valerate and dienogest before office operative hysteroscopy: a feasibility study

To investigate the impact of a 3 months preoperative administration of an oral contraceptive, containing dienogest (DNG) and estradiol valerate (E₂V) on the outcome of office operative hysteroscopy (OOH). One-hundred and forty-two patients diagnosed at office hysteroscopy as having an asynchronous endometrium associated with either a broad-base sessile endometrial polyp (>1.5, <2.5 cm) or a uterine septum (>1/3 uterine cavity) or scheduled for tubal sterilization were enrolled into a prospective case-control study at University “Federico II” of Naples. 86/142 patients accepted the preoperative hormonal treatment (Group A), while 56/142 refused, thus becoming controls (Group B). Group A underwent OOH during the 10th–20th days of the third cycle of treatment. In Group B OOH was performed at enrolment, together with the diagnostic procedure. The study outcomes were: endometrial pattern, success rate, operating time, degree of surgical difficulty and pain score. An overall improvement of the endometrium was reported in 100% of cases in Group A. A statistically significant difference in success rate could not be demonstrated between two groups. Operative procedures were performed significantly quicker and easier in Group A than Group B (p < 0.001 and p < 0.05, respectively). The mean Visual Analog Scale (VAS) score was significantly lower in Group A (p < 0.001). A short pretreatment with combined oral contraceptive (COC) containing E₂V/DNG seems to have a favorable impact on endometrium which in turn may result in an improvement of the overall outcomes of OOH.     

避孕节育干预项目对四川省流动人口避孕行为的影响

目的:评估避孕节育干预项目对四川省流动人口避孕行为的影响,为探索适宜的流动人口避孕行为干预模式提供依据。方法:多阶段随机整群抽取四川省成都市和攀枝花市流动人口相对集中的工厂、建筑工地、服务娱乐场所,并随机分为干预组和对照组。采用结构式问卷对2197名18～49岁流动人口进行干预前、后的调查。结果:干预后,干预组对象选择使用避孕套作为避孕方法的比例增加了5.32%;紧急避孕药的使用比例从干预前的13.22%上升至23.05%(P<0.01);干预组寻求咨询服务的比例为60.46%,与干预前相比提高了41.76%(P<0.01)。结论:干预后流动人口选择使用避孕套的比例以及紧急避孕药的使用比例都有所上升,对象寻求咨询服务的行为得到促进,但今后还应继续加强对低学历人群和未婚流动人口避孕节育的宣传教育和咨询服务。     

Psychological effect of the oral contraceptive formulation containing 3 mg of drospirenone plus 30 microg of ethinyl estradiol

OBJECTIVE: To investigate in healthy eumenorrheic young women whether an oral contraceptive (OC) containing drospirenone (DRSP) (3 mg) + ethinyl estradiol (EE) (30 microg) (DRSP + EE) could modify psychological symptoms and whether it could modify steroids interfering with the gamma-aminobutyric acid (GABA)-A receptors. DESIGN: Clinical study of treated subjects and nontreated controls. SETTING: Healthy volunteers in the Department of Obstetrics and Gynecology at Cagliari University. PATIENT(S): Control group (n = 12) and OC group (n = 10) women with similar age, body mass index, and main outcome measures. INTERVENTION(S): The control group was studied during the first menstrual cycle at the follicular phase (FP) and at the luteal phase (LP) and during the third cycle at the LP; the OC group was studied during the first cycle, as described above, and on day 16-18 of the third cycle of treatment with DRSP + EE. MAIN OUTCOME MEASURE(S): Psychometric scale (SCL-90), DHEAS, P, allopregnanolone (AP), and allotetrahydrodeoxy-corticosterone (THDOC). RESULT(S): SCL-90 and DHEAS did not vary throughout the menstrual cycle. P, AP, and THDOC values were higher during the LP than the FP. At the third cycle, in the control group the main outcome measures were similar to those at LP. In the OC group, the SCL-90 global score, the intensity of anxiety and phobic anxiety, the levels of anxiolytic steroids (P, AP, THDOC) and the anxiety-inducing steroid DHEAS were reduced. CONCLUSION(S): The results suggest beneficial effects of DRSP + EE on psychological symptoms by decreasing DHEAS.     

Inhibition of oral contraceptive steroid—metabolizing enzymes by steroids and drugs

The major 17α-ethinyl estradiol 2-hydroxylase is humans is the hepatic enzyme cytochrome P-450 IIIA4 (P-450NF), which is known to be inducible by rifampicin or barbiturates. The literature indicates that 17β-estradiol, progesterone, and norgestrel are competitive inhibitors and that primaquine and tolbutamide are rather weak noncompetitive inhibitors. Recent experiments in this laboratory indicate that gestodene is a relatively potent mechanism-based inactivator of cytochrome P-450 IIIA4 in vitro. Inhibition requires incubation with the reduced form of nicotinamide adenine dinucleotide phosphate, is time and concentration dependent, and can be partially blocked by the presence of noninhibitory cytochrome P-450 IIIA4 substrates. The in vitro activation by gestodene provides a possible explanation for the increase in plasma estrogen levels reported in women administered gestodene along with 17α-ethinyl estradiol.     

The effects of two gonane progestins alone and in combination with ethinyl estradiol on serum lipoproteins

Twenty women, oophorectomized as part of the treatment for cervical carcinoma in an early stage but otherwise healthy, participated in the study. Ten of them were given desogestrel (DG) 150 micrograms/day for 3 wk followed by DG + 30 micrograms ethinyl estradiol (EE) for 6 wk, and finally EE alone for 3 wk. The other ten women were given 150 micrograms levonorgestrel (NORG) and EE in a similar way. Before treatment and after each period, total and free cholesterol (TC, FC) triglycerides (TG) and phospholipids (PL) were assayed in serum and in the ultracentrifugally isolated lipoprotein fractions very low, low and high density lipoproteins (VLDL, LDL and HDL). The results indicate that both progestins induced the same 'androgenic' pattern when given alone, i.e. a decrease in serum- and HDL-TC and a decrease in VLDL-lipids. In combination with EE, however, DG seems to counteract the effects of EE to a lesser extent than NORG, as judged particularly from the effects on TG and PL in serum and VLDL.     

Factors influencing discontinuation of intrauterine contraceptive devices: an assessment in the Indian context

Sociocultural and behavioral factors are associated with decision to use and the selection of a contraceptive method, continuation of use and reasons for discontinuation of a contraceptive. This paper tries to distinctly outline the determinants of discontinuation of the intrauterine contraceptive device (IUCD), especially in the Indian context. Data on medical reasons for discontinuation are available through clinical trials. However, sociodemographic studies provide one with a wider spectrum to analyze the factors associated with the discontinuation of IUCDs. Information on service providers can be used to improve the quality of family planning services in the country. In India, a thorough review of birth spacing methods, especially the IUCD, is needed since the surveys show a high rate of discontinuation. The emphasis in this paper is upon compilation of reasons for discontinuation of the IUCD and research thereof. The review of the literature is directed towards giving a new direction to assessment of family planning programs, especially in India where population control is largely dependent upon permanent methods. Delineation of factors is important to improve the family planning program.     

Effect of cost on early removal of contraceptive implants: a prospective cohort study

Objectives: To evaluate the effect of the cost of subdermal etonogestrel implant (SEI) on the continuation rate one year after insertion, and to assess the reasons given by users to remove the implant before the expiration date.

Methods: Prospective cohort study conducted among 265 women who chose the SEI as a contraceptive method in a sexual and reproductive health center in the eastern region of Spain, between October/2012 and October/2017. The sample was divided into two cohorts depending on the cost of the implant for the user (free-of-charge or requiring partial payment). Kaplan–Meier survival curves were used to compare the cumulative removal rates of free implants with partially paid implants within the first year of insertion. Cox proportional hazards models were used to control for confounders.

Results: After adjusting for confounders, no significant associations were found between the cost of the implant and its removal within a year of insertion. No significant associations were found in the reasons given for implant removal and for the duration of implant use.

Conclusions: Cost was not associated with SEI continuation rates within the first year of use. No other significant variables were found to explain implant removal within one year of use.     

Ethnic variation in estradiol metabolism in reproductive age Asian and white women treated with transdermal estradiol

Asian women have significantly higher serum E(2) levels during treatment with transdermal E(2) compared with white women. This finding suggests altered metabolic clearance of this steroid hormone.