Effect of oral versus transdermal steroidal contraceptives on androgenic markers

OBJECTIVE: The purpose of this study was to compare biochemical androgen profiles in women treated with the contraceptive patch versus an oral contraceptive (OC). STUDY DESIGN: Twenty-four healthy women were randomly assigned to receive 3 cycles of either the contraceptive patch (ethinyl estradiol [EE] 20 microg/d and norelgestromin 150 microg/d) or OC (EE 35 mug and norgestimate 250 microg). Blood samples were taken at baseline and end of treatment. Serum levels of sex hormone-binding globulin (SHBG), total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), and 3alpha-androstanediol glucuronide (3alpha-diol G) were quantified by immunoassay methods; free T was calculated. The paired t and Student t tests were used for statistical analysis. RESULTS: Nineteen women completed the study (patch, n = 10; OC, n = 9). Despite a 1.6-fold relative increase in SHBG levels with the patch versus OC (449% vs 274%, P = .03), free T decreased equally in both groups (patch 60%, P < .0001; OC 59%, P < .0001). DHEAS decreased by 26% in the patch group (P < .01) and 32% in the OC group (P < .001). 3alpha-diol G was reduced by 52% in the patch group (P < .0001) and 51% in the OC group (P < .0001). In addition, the OC was associated with significant decreases in A and DHT. CONCLUSION: The contraceptive patch had an effect comparable to the OC on several key androgenic markers. Given these biochemical findings, the contraceptive patch has significant potential as a therapeutic agent for disorders of androgen excess.     

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.     

The effect of multivitamin supplements on continuation rate and side effects of combined oral contraceptives: A randomised controlled trial

Abstract

Objectives This study aimed to assess the effect of multivitamin use during the pill-free interval on the continuation rate and side effects of combined oral contraceptives (COCs) within the first few cycles of use.

Methods In this trial, 332 women presenting to public health centres in an Iranian city each received a COC pack containing 21 pills and were randomised to one of three groups: two of the groups also received 42 multivitamin pills or 42 placebo pills to be taken once a day for 7 days before starting COCs and again during the 7-day pill-free interval for five cycles, while the third group received no multivitamin or placebo pills with their COCs. The groups were compared using Cox regression and χ² tests.

Results There were no losses to follow-up. Continuation rates at the sixth cycle were 88% for the multivitamin group, 75% for the placebo group and 67% for the no intervention group. Compared with the multivitamin group, the six-cycle discontinuation rate was significantly higher in the placebo group (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.15–4.45; p = 0.019) and no intervention group (HR 3.15, 95% CI 1.66–5.99; p < 0.001). Nausea, mood changes, weight gain and breast tenderness were significantly less common in the multivitamin group than in the other groups in all cycles, and spotting/irregular bleeding and dizziness were significantly less common in most of the second, third and sixth cycle follow-up.

Conclusions Multivitamin supplements could significantly reduce the side effects of COCs in the initial cycles and improve continuation rates. However, the study limitations do not allow for any definite conclusion for their use in clinical practice, especially in communities rich in nutrients.

Chinese Abstract

摘要

目的：本研究旨在评估在不服避孕药的间歇期口服多种维生素对续用率的影响,及服用复方避孕药（COCS）最初几个周期的副作用。

方法：在这项试验中,在伊朗城市代表公众健康中心的332名女性均收到含有21粒药物的复方口服避孕药包,并被随机分到3组。其中2组的妇女还分别收到了42粒维生素或42粒安慰剂,这些药物需要在服用口服避孕药之前及不同周期的间歇期内每天服用1次,连续服用7天;第三组只有复方口服避孕药。不同组之间用COX回归及卡方检验进行比较。

结果：目前还没有丢失的随访。三个组在第六个周期的续用率分别为：口服维生素组88%,口服安慰剂组75%,无干预组67%。与口服多种维生素组比较,口服安慰剂组在第六周期的停药率明显高（HR2.26,95%CI1.15-4.45;p=0.019）,无干预组的停药率也明显高于口服维生素组（HR 3.15, 95% CI 1.66 ? 5.99; p = 0.001）。在所有周期中,恶心、情绪变化、体重增加及乳房触痛在维生素组明显少于其他2组,瘀点、不规则出血、眩晕在第二、三、六周期很少见。

结论：多种维生素的应用可以显著降低开始口服复方避孕药的最初几个周期内的副作用,同时可以提高续用率。然而,由于这篇文章的限制,并无明确结论支持他们广泛应用于临床,尤其是在有丰富营养物质的社区。

关键词：副作用,复方口服避孕药,续用率,维生素     

Androgen and lipid profiles in adolescents with polycystic ovary syndrome who were treated with two forms of combined oral contraceptives

OBJECTIVE: To compare the effects of cyproterone acetate and desogestrel, as part of combined oral contraceptives, on lipid metabolism and hirsutism of adolescents with polycystic ovary syndrome (PCOS). DESIGN: Prospective randomized clinical trial. SETTING: Outpatient gynecology clinic (referral center) of a university. PATIENT(S): Twenty-eight adolescent girls with clinical and biological hyperandrogenism and six or less menses during the past 12 months. INTERVENTION(S): Group A (n = 14) received 0.15 mg of desogestrel plus 0.030 mg of ethinyl estradiol daily. Group B (n = 14) received 2 mg of cyproterone acetate plus 0.035 mg of ethinyl estradiol daily. Treatment was given for 21 days followed by a 7-day rest for a period of 12 months. MAIN OUTCOME MEASURE(S): Hirsutism and lipid profile were evaluated before initiation and at 3, 6, 9, and 12 months of treatment. Androgen profile was evaluated before and at 12 months of treatment. RESULT(S): A significant decline of the Ferriman-Gallway hirsutism score was observed from the sixth month of therapy in both groups. During therapy, the levels of testosterone, free testosterone, Delta(4)-androstenedione, and 17OH-progesterone decreased significantly, whereas sex hormone-binding globulin (SHBG) increased significantly in both groups. The level of total cholesterol and low density lipoprotein (LDL) cholesterol increased significantly, whereas high density lipoprotein (HDL) cholesterol and apolipoprotein A-I increased significantly from the third month of therapy in both groups. Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios remained unchanged. The levels of triglycerides increased significantly in the cyproterone acetate-treated group after the third month. CONCLUSION(S): Treatment of adolescent girls with PCOS with the two studied formulations is comparably effective in decreasing hirsutism and androgen levels. Both combined oral contraceptives are associated with an increase of total cholesterol, LDL cholesterol, and HDL cholesterol levels and no change of the total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios. Treatment with the cyproterone acetate combined oral contraceptive is associated with a tendency toward increasing the levels of triglycerides.     

The effects of age,body mass index,smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives

Objectives To investigate the factors associated with idiopathic venous thromboembolism in combined oral contraceptive users and to estimate the crude and age-specific incidence rates of idiopathic venous thromboembolism among this population.

Methods The UK MediPlus Database and the General Practice Research Database were searched to identify women with evidence of venous thromboembolism while exposed to combined oral contraceptives. Cohort and nested case-control studies were carried out using the same methodology on both databases. We conducted a meta-analysis using the individual data for the cases and controls from the two case-control studies to identify factors associated with idiopathic venous thromboembolism in women using combined oral contraceptives.

Results The incidence rate of idiopathic venous thromboembolism among oral contraceptive users was 39.4 per 100 000 exposed woman-years. The age-specific incidence rates were found to rise sharply after the age of 39 years. Factors identified as being significantly associated with idiopathic venous thromboembolism in women using combined oral contraceptives were: body mass index of 25 kg/m² and over, the association rising dramatically in women with a body mass index of 35 kg/m² or more; smoking; general ill health; and asthma.

Conclusion We believe that, before prescribing combined oral contraceptives, the venous as well as the arterial factors need to be considered and, in addition, age, obesity and smoking are all relevant when assessing an individual patient's risk.     

The effect of a drospirenone-containing combined oral contraceptive on female sexual function: a prospective randomised study

Objectives: The study investigated the effects on female sexual function of a progestogen-containing combined oral contraceptives (COCs) with an antiandrogenic profile taken in a continuous regimen.

Methods: In this prospective randomised single-institution study, 80 healthy women with a monogamous partner and an active sexual life were randomised into two groups for a period of 3 months. Women in the exposed group (n?=?40) took a COCs containing 30?μg ethinylestradiol (EE) and 3?mg drospirenone (DRSP) in a 21/7 regimen. Women in the control group (n?=?40) used either a barrier contraceptive method (BCM) or a natural family planning method (NFPM). Participants were asked to complete a set of validated questionnaires to assess sociodemographic variables and measure Female Sexual Function Index (FSFI).

Results: The total FSFI score (p?p?=?0.04) and arousal (p?=?0.03) scores, were significantly lower in the COCs group after 3 months of hormonal contraceptive use compared with baseline. Women using BCM or NFPM showed an improvement in total FSFI score (p?=?0.02). Hormonal contraception with DRSP increased the likelihood of worse sexual function in the desire (odds ratio [OR] 2.47; 95% confidence interval [CI] 1.22, 4.98; p?=?0.01) and arousal domains (OR 2.85; 95%CI 1.34, 5.93; p?=?0.005) and in total FSFI score (OR 2.01; 95%CI 1.45, 2.79; p?Conclusions: The study found evidence that women taking a combined EE/DRSP COCs for 3 months may have a worsening of sexual function as measured by FSFI.     

Adverse mood effects of combined oral contraceptives in relation to personality traits

Objective

Mood symptoms, such as depressed mood, anxiety and increased irritability, remain one of the major reasons for discontinuation of combined oral contraceptive (COC) pills. The aim of this study was to compare personality traits in women with ongoing or previous use of COCs and different experiences from these compounds with respect to adverse mood symptoms.

Study design

Thirty women currently on COCs with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 33 women who had discontinued COC use due to adverse mood effects were included. All participants were asked to fill out the Swedish universities Scales of Personality (SSP) to assess different personality traits.

Results

The women who were experiencing mood-related side effects on their current COC use exhibited higher scores on the somatic anxiety and stress susceptibility traits as compared to the women who did not experience any mood-related side effects from their current COCs. Women who had discontinued COC treatment because of adverse mood effects had higher scores of detachment and mistrust compared to women who had discontinued COC for reasons unrelated to mood effects.

Conclusion

Higher scores on specific personality traits such as somatic anxiety and stress susceptibility are found in women with ongoing experience of adverse mood symptoms from COC. Higher scores of mistrust and detachment are more common among women who have discontinued COC treatment due to adverse mood effects.     

Pharmacokinetics of the contraceptive steroids levonorgestrel and gestodene after single and multiple oral administration to women

Little is known about the pharmacokinetics of the two progestins levonorgestrel and gestodene during long-term administration compared with single-dose pharmacokinetics. The predictive value of single-dose administration for the pharmacokinetic behavior of a progestin during long-term treatment was investigated for two triphasic oral contraceptives. One contained levonorgestrel and the other gestodene, each in combination with ethinyl estradiol. In eight Japanese women who received the levonorgestrel-containing formulation over a treatment cycle, steady-state trough levels of levonorgestrel were higher than those obtained by computer simulation based on single-dose administration. An analogous observation was made in a group of 10 white women who received the gestodene-containing formulation. A close correlation between gestodene and sex hormone-binding globulin concentrations was demonstrated for eight subjects; the other two patients already had initially high sex hormone-binding globulin levels. Ethinyl estradiol-induced production of sex hormone-binding globulin seems to be a major factor that contributes to the accumulation of the two progestins in the plasma. Computer simulation, based on single-dose pharmacokinetics, allows an estimation of this contribution.     

Concerns on future fertility among users and past-users of combined oral contraceptives: a questionnaire survey

Abstract

Objective: The combined oral contraceptive pill is the most preferred contraceptive method worldwide. Despite high life-time prevalence of infertility of 16–26%, scarce data about concerns of future fertility among COC users are available. We aimed to study whether COC usage induces concerns about fertility.

Methods: Online questionnaire-based survey included 1283 current COC users and 1006 past users. The questionnaire covered knowledge and concerns of various aspects of fertility with respect to COC usage.

Results: Significantly, more current users (66%) than past users (52%) had considered whether or not COC usage could affect future fertility (OR?=?1.6, 95% CI 1.3–1.9). Nearly 50% of both groups believed COC usage could impair conception rates after discontinuation. Furthermore, 28% current vs. 19% past users believed COC could diminish the ovarian reserve more permanently. Conversely, 14% current and 11% past users believed that lack of ovulation could ‘spare’ the eggs (OR?=?0.9, 95% CI 0.7–1.3). Significantly fewer current users (22%) vs. past users (35%) had heard, primarily by female friends, that a short break of 1–2 months during long-term COC usage was healthy, (OR 0.72, 95%CI?=?0.56–0.92).

Conclusions: Health care professionals prescribing hormonal contraception should be aware of misapprehensions and concerns of fertility among users of COC.     

Effects of combined oral contraceptives on the clinical and biochemical parameters of hyperandrogenism in patients with polycystic ovary syndrome: a systematic review and meta-analysis

Introduction: Nowadays, selection of COCs with maximum antiandrogenic effects is one the main issues in treatment of women with polycystic ovary syndrome (PCOS).

Objective: This systematic review and meta-analysis aimed to compare the effects of COCs on the clinical and biochemical parameters of hyperandrogenism (HA) in patients with PCOS.

Methods: Electronic databases (PubMed, Scopus, ScienceDirect and web of science) were searched from 1987 to November 2015 to identify clinical trials investigating effect of the various COCs on the clinical and biochemical parameters of HA in patients. In this meta-analysis, both fixed and random effect models were used. Potential sources of heterogeneity were explored by meta-regression and subgroup analyses.

Results: Findings showed that COC use for 3–12 months was significantly associated with an increase in sex hormone-binding globulin (SHBG) levels and a decrease in Ferriman–Gallwey (FG) score, total testosterone (TT), free testosterone (FT), androstenedione (A4) and dehydroepiandrosterone sulphate (DHEAS) levels. Type of progestin or duration of treatment had no important effects on declining androgen levels. Long-term use of COCs (6–12 months) was more effective in improving hirsutism, compared to short term. COCs containing cyproterone acetate (CPA) for 12 months had the strongest effect in improving hirsutism.

Conclusions: This study shows that, in patients with PCOS, COCs can effectively improve biochemical and clinical parameters of HA. All COCs studies have similar effects on the hormonal profiles of these patients, and products containing CPA may be an effective treatment in hirsute patients with PCOS.     

Women’s ability to self-screen for contraindications to combined oral contraceptive pills in Tanzanian drug shops

Objective

To estimate the accuracy of self-screening for contraindications to combined oral contraceptive pills (COCs) and to estimate the proportion of women with contraindications to hormonal methods among those using drug shops in Tanzania.

Methods

Trained nurses interviewed 1651 women aged 18–39 years who self-screened for contraindications to COCs with the help of a poster at drug shops in Tanzania. Nurse assessment of the women served as the gold standard for comparison with self-assessment. Blood pressure was also measured onsite.

Results

Nurses reported that 437 (26.5%) women were not eligible to use COCs, compared with 485 (29.4%) according to self-report. Overall, 133 (8.1%) women who said that they were eligible were deemed ineligible by nurses. The rate of ineligibility was artificially high owing to participant and nurse assessments that were incorrectly based on adverse effects of pill use and cultural reasons, and because of the sampling procedure, which intercepted women regardless of their reasons for visiting the drug shop. Adjusted rates of ineligibility were 8.6% and 12.7%, respectively, according to nurse and participant assessment. Both nurses and women underestimated the prevalence of hypertension in the present group.

Conclusion

Self-screening among women in rural and peri-urban Tanzania with regard to contraindications to COC use was comparable to assessment by trained nurses.     

Influence of third-generation oral contraceptives on the complexity analysis and symbolic dynamics of heart rate variability

ABSTRACT

Objective To evaluate the influence of oral contraceptives (OCs) containing 20 μg ethinylestradiol (EE) and 150 μg gestodene (GEST) on the autonomic modulation of heart rate (HR) in women.

Methods One-hundred and fifty-five women aged 24 ± 2 years were divided into four groups according to their physical activity and the use or not of an OC: active-OC, active-non-OC (NOC), sedentary-OC, and sedentary-NOC. The heart rate was registered in real time based on the electrocardiogram signal for 15 minutes, in the supine-position. The heart rate variability (HRV) was analysed using Shannon's entropy (SE), conditional entropy (complexity index [CInd] and normalised CInd [NCI]), and symbolic analysis (0V%, 1V%, 2LV%, and 2ULV%). For statistical analysis the Kruskal-Wallis test with Dunn post hoc and the Wilcoxon test (p < 0.05 was considered significant) were applied.

Results Treatment with this COC caused no significant changes in SE, CInd, NCI, or symbolic analysis in either active or sedentary groups. Active groups presented higher values for SE and 2ULV%, and lower values for 0V% when compared to sedentary groups (p < 0.05).

Conclusion HRV patterns differed depending on life style; the non-linear method applied was highly reliable for identifying these changes. The use of OCs containing 20 μg EE and 150 μg GEST does not influence HR autonomic modulation.     

The role of combined oral contraceptives in the management of acne and seborrhea

Acne and seborrhea (or facial oiliness) are related androgenic skin disorders which affect a high proportion of women after menarche. They can have a negative effect on psychological well-being and social life. Androgens play an important role in the pathogenesis of acne through the stimulation of sebum secretion, increasing sebaceous gland size and possibly through follicular hyperkeratinization. Conversely, estrogens decrease sebum production by suppressing gonadotropin release and androgen production and increasing sex hormone binding globulin production.

One of the treatment options for these conditions is hormonal therapy, especially for women who require contraception. The effect of combined oral contraceptives in androgenic skin disorders depends on their estrogen?:?progestogen balance and on the antiestrogenic activity of the progestogen component.

Improved understanding of what women value about oral contraceptives suggests that the choice of product should be tailored as much as possible to the individual. Several combined oral contraceptives containing new-generation progestogens (e.g. desogestrel, gestodene) or progestational antiandrogens (e.g. cyproterone acetate, chlormadinone acetate) have demonstrated efficacy in the treatment of women with acne, although comparisons between trials are difficult because of differing endpoints. Seborrhea has been less well studied, but the few studies that are available show an improvement in women with this condition using combined oral contraceptives.