Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial.

STUDY QUESTION: Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only? SUMMARY ANSWER: The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation. WHAT IS KNOWN ALREADY: EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking. STUDY DESIGN, SIZE, DURATION: This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics. MAIN RESULTS AND THE ROLE OF CHANCE: Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay. LARGE SCALE DATA: Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction). LIMITATIONS, REASONS FOR CAUTION: The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results. WIDER IMPLICATIONS OF THE FINDINGS: The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens. STUDY FUNDING/COMPETING INTEREST(S): Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02352090. TRIAL REGISTRATION DATE: 27 January 2015. DATE OF FIRST PATIENT'S ENROLMENT: 1 April 2015.

Differential Effect of 2 Hormonal Contraceptives on the Relative Telomere Length of Youth With Type 1 Diabetes.

Context: Adolescents and young women (AYA) with type 1 diabetes (T1D) may require hormonal contraception for an extended period. However, it is unclear what effect hormonal contraception has on telomere length, a marker of the risk for complications. Objective: To investigate the relative telomere length (RTL) in AYA with T1D (AYA-T1D) and healthy young women (AYA-C) after 18 months of combined oral contraception use (COC) with ethinyl estradiol/desogestrel, or a subdermal etonogestrel implant (IM). Methods: A nonrandomized prospective study was performed in which 39 AYA-T1D and 40 AYA-C chose the COC or the IM. RTL was measured by monochrome multiplex-quantitative PCR in DNA from peripheral blood mononuclear cells (PBMC). The impact of contraceptives and clinical variables on RTL was assessed using lineal regression analysis. Results: Longer RTL compared to baseline was observed in AYA-T1D (P < .05) and AYA-C (P  < .01) after using the IM. However, the total of AYA and the AYA-C group treated with COC decreased RTL after 18 months of treatment compared to baseline (P < .05). The type of contraceptive used was determinant for the changes in RTL compared to baseline in all subjects and controls (P ≤ .006). For AYA-T1D, HbA1c levels were not associated with RTL, but the high-sensitivity C-reactive protein was negatively related with the changes in RTL at 18 months compared to baseline (standardized R2 : 0.230, P  = .003). Conclusion: IM was associated with longer RTL in AYA-T1D and AYA-C. In contrast, a shortening of telomere length in PBMC was observed after using COC.

Cardiometabolic Effects of Cabergoline and Combined Oral Contraceptive Pills in Young Women with Hyperprolactinemia: A Pilot Study.

Although dopaminergic agents are the drugs of choice in treatment of prolactin excess, women who cannot be treated with these agents are recommended to receive estrogen preparations. The aim of this study was to compare cardiometabolic effects of both treatment options. The study population included three groups of young women. Subjects with mild-to-moderate hyperprolactinemia received either low-dose cabergoline or oral combined contraceptives (ethinyl estradiol plus desogestrel), while normoprolactinemic women were drug-naive. Plasma prolactin, glucose homeostasis markers, lipids, circulating levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine, and the urinary albumin-to-creatinine ratio (UACR) were assessed at entry and six months later. Hyperprolactinemic women differed from normoprolactinemic ones in glucose homeostasis markers, high-density lipoprotein (HDL)-cholesterol, triglycerides, uric acid, hsCRP, fibrinogen, homocysteine and UACR. Cabergoline decreased total and monomeric prolactin levels, which was accompanied by normalization of glucose, insulin sensitivity, glycated hemoglobin, HDL-cholesterol, triglycerides, uric acid, hsCRP, fibrinogen, homocysteine and UACR. Despite a neutral effect on prolactin levels, combined contraceptives worsened insulin sensitivity and increased triglycerides, hsCRP, fibrinogen and UACR. At follow-up, cabergoline-treated women were characterized by a better cardiometabolic profile than women receiving ethinyl estradiol plus desogestrel. Our findings suggest that only cabergoline reduces cardiometabolic risk in young women with hyperprolactinemia.

Effects of estradiol- and ethinylestradiol-based contraceptives on adrenal steroids: A randomized trial.

OBJECTIVES: Ethinylestradiol (EE)-based combined oral contraceptives (COC) affect adrenal function by altering steroid and corticosteroid-binding globulin (CBG) synthesis that may contribute to adverse effects related to these drugs. The effects of COCs containing natural estrogens remain unclear. We compared the effects of COCs containing estradiol valerate (EV) and EE on cortisol and other adrenal steroid hormones. STUDY DESIGN: A spin-off study of a randomized, open-label trial. Fifty-nine healthy women were allocated to groups that engaged in the continuous use of EV+dienogest (DNG), EE+DNG, or DNG only for 9 weeks. We measured changes in adrenal steroids, CBG, and the free cortisol index (FCI). RESULTS: Treatment with EE+DNG increased total cortisol (mean increment 668 nmol/L, p < 0.001) and cortisone (10 nmol/L, p= 0.001) levels, whereas the change from the baseline was insignificant for the EV+DNG and DNG-only groups. Dehydroepiandrosterone sulfate decreased by 24% in the EE+DNG group but remained unchanged in the EV+DNG and DNG-only groups. Aldosterone and 17-hydroxyprogesterone levels did not differ between the groups. All preparations increased CBG, but the increase in the EE+DNG group (median increment 42 µg/mL, p < 0.001) was 9- and 49-fold higher than that in the EV+DNG and DNG-only groups, respectively. The FCI remained unchanged in all study groups, indicating that cortisol and CBG mainly increased in parallel, although some individuals demonstrated larger alterations in the cortisol-CBG balance. CONCLUSION: In COCs, EV had a milder effect on circulating CBG and adrenal steroid levels than EE; however, further research is necessary to determine the long-term effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT02352090 IMPLICATIONS: EV-based COC had reduced effects on circulating CBG and adrenal steroids compared to EE, probably due to a lower hepatic impact. Whether the sensitization of the adrenals to ACTH varies according to COC contents and whether it relates to experienced side effects needs to be investigated. These results encourage further research and development of contraceptives containing natural estrogens.

Factors affecting the choice of drospirenone as the component of combined contraceptive pill in daily clinical practice: the results of nation-wide survey.

OBJECTIVES: The aim of the multicenter, open-label, post-marketing, observational survey was to assess doctors' preferences in choosing the progestogen component of the combined contraceptive pill (CCP) and factors affecting this choice in daily clinical practice as well as non-contraceptive reasons use of CCP containing drospirenone (CCPD) and patients' tolerance and satisfaction with the treatment. MATERIAL AND METHODS: This multicenter, open-label, post-marketing, survey was performed nation-wide with the participation of 222 doctors involving and 10,345 patients treated with CCPD. The study questionnaire included questions concerning factors affecting the choice of drospirenone as a component of CCP and assessing prescription pattern of the drug as well as tolerance and satisfaction with the use of CCPD. RESULTS: The doctors frequently declared their choice of drospirenone as the progestogen component of CCP. The most important factors affecting the choice of drospirenone, declared by doctors, were tolerance level, consistent regulation of menstrual cycle and not causing spotting. CCPD was prescribed to patients with irregular menstrual cycles (62.7%) and painful menstruation (46.8%). During follow-up, significantly increased percentage of patients assessed the tolerance of treatment with CCPD as very good (52.5% vs 68.0%; p < 0.01) and very satisfied with its use (61.9% vs 77.8%, p < 0.01). CONCLUSIONS: 1) Drospirenone is frequently chosen progestogen component in CCP by Polish gynecologists due to its good tolerance, consistent regulation of the menstrual cycle and no spotting in patients opinion. 2) CCPD was most frequently used in patients with irregular menstrual cycles and painful menstruation. 3) The patients were satisfied with the use CCPD and treatment was well tolerated.

Effect of combined contraceptive pill on immune cell of ovarian endometriotic tissue.

BACKGROUND: Dysregulation of immune response is associated with development of endometriosis. The study aim was to evaluate effect of combined oral contraceptive pills (COCs) consisting of ethinyl estradiol (EE) and desogestrel on the expression of macrophage, natural killer cells, and regulatory T cells of ovarian endometriotic cysts. METHODS: Endometriotic cyst wall tissues were collected from women with endometriosis who were treated (n = 22) with COCs (one table per day of EE 0.03 mg and desogestrel 0.15 mg administered for 28 to 35 days before surgery) or untreated (n = 22). The tissues were collected from endometriotic cyst wall during laparoscopic or laparotomy ovarian cystectomy. Immunohistochemistry for anti-CD68, anti-CD56, and anti-forkhead-winged helix transcription factor (FoxP3), a marker for macrophages, natural killer cells, and regulatory T cells, respectively, were investigated. RESULTS: The median (interquartile range [IQR]) number of anti-CD68 positive cells in the COC group was significantly lower than in the untreated group (12.7; 4.9-19.3) versus 45.7 (26.0-70.7), p < 0.001). Tissue infiltration of anti-CD56 positive cells in endometriotic cyst was significantly higher after the treatment when compared with tissue from untreated group (42.9, 27.4-68.9 versus 25.3 (14.1-37.3; p = 0.009). The number of regulatory T cells was also significantly increased in the COC group (6.3, 2.8-15.5) versus 0 (0-1.8; p < 0.001). CONCLUSIONS: The effects of COC, containing EE 0.30 mg with desogestrel 0.15 mg, on the immune system was demonstrated by a significant decrease in the number of macrophages and an increase in natural killer and regulatory T cells.

[Effectiveness and use of hormonal contraceptives (except for intrauterine devices): CNGOF Contraception Guidelines]. / Contraception hormonale en pratique hors dispositifs intra-utérins. RPC Contraception CNGOF.

Hormonal contraceptives remain among the most popular methods used by women. The purpose of this work is to review the effectiveness and use of these different methods. In addition, some side-effects are feared and/or frequently reported by users of hormonal contraceptives: unscheduled bleeding, acne, catamenial migraines, weight gain, libido and/or mood disorders. In this review of the literature, the accountability of hormonal contraceptives for the occurrence of some of these side-effects was discussed and a management strategy was proposed.

Evaluating the efficacy and safety of a progestin- and estrogen-releasing ethylene vinyl acetate copolymer contraceptive vaginal ring.

INTRODUCTION: Multiple studies confirm the safety and efficacy of the combined ethinyl estradiol (EE) and etonogestrel contraceptive vaginal ring (NuvaRing®). Advantages of continuous drug delivery through the vagina compared to oral administration include stable levels of contraceptive steroids without the need for daily drug administration. Although the combined contraceptive vaginal ring (CCVR) avoids the problem of missed pills, clinical data do not support greater efficacy. Vaginal administration avoids first-pass hepatic effects; however, EE is a potent inducer of hepatic globulins regardless of the route of administration. Consequently, thromboembolic risk during CCVR use is similar to that with combined oral contraceptives. Some epidemiologic and database studies suggest that the risk of thromboembolism is increased among users of the CCVR compared to levonorgestrel-containing combined pills. AREAS COVERED: This review examined the available literature for level 1 and level 2 evidence of the CCVR and its associated efficacy and safety. Studies are presented in table format with significant findings and conclusions described. EXPERT OPINION: A prospective study with 33,235 woman-years of exposure and with greater ability to control for covariates did not demonstrate an elevation of risk. The safety profile of the CCVR appears to be the same as with other combined hormonal contraceptives.

Comparison study on effectiveness of pentoxifyllin with LD to prevent recurrent endometriosis.

BACKGROUND: About 75% of the symptomatic patients who involved with endometriosis have pelvic pain and dysmenorrhea. Pentoxifyllin is one of the drugs that according to its mechanism could be effective for pain relief of endometriosis which has been used for endometriosis treatment recently. OBJECTIVE: We conducted a comparative study for detecting the effect of pentoxifylin (as an immonomodelator) in preventing recurrence endometriotic pain with pentoxifylin plus a combined contraceptive pill with low dose estrogen (LD) and also the LD pill alone. MATERIALS AND METHODS: This was a comparative clinical trial on 83 patients with the chief complaint (CC) of pain (dysmenorrheal /or pelvic pain) and with the end diagnosis of endometriosis, in an operative laparoscopy. Patients, dividing to 3 groups, were treated with pentoxifylin, pentoxifylin+LD and LD alone for 10 months. The severity of pain (dismenorhea and/or pelvic pain) was detected by visual analogue scale (VAS) before and after the treatment. The severity of endometriosis in the patients was: I in class I and II in class II and III in class III. The groups were matched for the pain. The number of the patients in group 1, 2 and 3 were 28, 28 and 27 respectively. RESULTS: The pain was reduced in the groups of pentoxifylin+LD (p<0.001) and LD alone (p=0.00). The pain relief was not significant in the group of pentoxifylin alone (p=0.136). After treatment, the severity of pain was not significantly different between the LD group and the LD+penthoxyfillin group, but there was difference between these two groups and the group of penthoxyfillin alone. CONCLUSION: This study showed that penthoxyfillin actually could not have any effect on the pain relief of endometriosis. It also made it clear that penthoxyfillin could not increase the efficacy of LD when used with this medication.

Serum Folate and Cobalamin Levels in Women Using Combined Contraceptive Vaginal Ring.

Purpose: The aim of our study was to evaluate the effects of combined contraceptive vaginal rings on serum concentrations of folate and cobalamin in healthy users. Material and Methods: Case-control study on cobalamin and folate status of 45 healthy female nulligravidae using a combined contraceptive vaginal ring for > 3 months and 45 healthy controls. Factors interfering with vitamin metabolism were thoroughly controlled. Results: Cobalamin and folate levels did not differ between the groups. Vegetarian diet, smoking or obesity did not have a significant influence. Conclusions: The use of a combined contraceptive vaginal ring provides an appropriate hormonal contraception in women with pre-existing cobalamin deficiency or restrictive diet habit in order to avoid interferences between vitamin B12 metabolism and exogenously applied estrogens.

Deep vein thrombosis in a woman taking oral combined contraceptive pills.

Oral combined contraceptive pill (OCCP) is popular as birth control pills. Like all other drugs, they are not free from risks. Women taking certain types of OCCP have higher risk of developing deep vein thrombosis (DVT). A 29 year old married woman had taken OCCP for 3.5 months, developed deep vein thrombosis of left leg. Hereditary and acquired causes of DVT were excluded. She was treated with parenteral and oral anticoagulants simultaneously and was advised to discontinue OCCP. Initially the risk of blood clot was believed to be due to dose of estrogen but recent study relates it to the type of progesterone involved in OCCP. Thus, it is still a matter of debate, whether to associate risk of DVT to the amount of estrogen alone or also to the type of progestin. Apart from careful selection of patients, one should also look for the risk of venous thromboembolism irrespective of type of OCCP prescribed.