Insights into the Behavior of Triple-Negative MDA-MB-231 Breast Carcinoma Cells Following the Treatment with 17ß-Ethinylestradiol and Levonorgestrel.

Oral contraceptives (OCs) are widely used due to their efficiency in preventing unplanned pregnancies and treating several human illnesses. Despite their medical value, the toxicity of OCs remains a public concern. Previous studies indicate the carcinogenic potential of synthetic sex hormones and their link to the development and progression of hormone-dependent malignancies such as breast cancer. However, little is known about their influence on the evolution of triple-negative breast carcinoma (TNBC), a malignancy defined by the absence of estrogen, progesterone, and HER2 receptors. This study reveals that the active ingredients of modern OCs, 17ß-Ethinylestradiol, Levonorgestrel, and their combination induce differential effects in MDA-MB-231 TNBC cells. The most relevant behavioral changes occurred after the 24 h treatment with 17ß-Ethinylestradiol, summarized as follows: (i) decreased cell viability (64.32% at 10 µM); (ii) cell roundness and loss of confluence; (iii) apoptotic aspect of cell nuclei (fragmentation, membrane blebbing); and (iv) inhibited cell migration, suggesting a potential anticancer effect. Conversely, Levonorgestrel was generally associated with a proliferative activity. The association of the two OCs exerted similar effects as 17ß-Ethinylestradiol but was less effective. Further studies are necessary to elucidate the hormones' cytotoxic mechanism of action on TNBC cells.

Drospirenone: a Latin American perspective for oestrogen-free oral contraception.

AIM: Combined hormonal contraceptives, despite their high efficacy, are associated with an increased relative risk of cardiovascular events. The contraceptive mechanism of action of combined pills depends fundamentally on their progestin component. METHODS: A narrative review was performed. RESULTS: The drospirenone-only pill, including this synthetic progestogen with antimineralocorticoid and antiandrogenic activity, has high contraceptive efficacy that has been demonstrated with a 24-day schedule of 4-day administration of hormone-free pills. Due to its safety profile, the drospirenone-only pill is suitable even in high-risk populations, such as women with high blood pressure, thromboembolism, smoking or dyslipidemia. CONCLUSION: Considering the increasing prevalence of these comorbidities in Latin America, the 4 mg drospirenone-only pill is suggested as one of the strategies of choice in the region for those women who choose oral contraceptives.

Low dose combined oral contraceptives induced thrombotic anterior wall myocardial infarction: a case report.

BACKGROUND: Combined oral contraceptive pills are associated with an established risk for venous thrombosis; however, their risk for arterial thrombosis remains uncertain, especially with the development of low dose new generations of combined oral contraceptive. Arterial thrombosis is less likely to occur with the use of oral contraceptive pills in the absence of cardiovascular risk factors. CASE PRESENTATION: We report a 35-year old female with no cardiovascular risk factors who presented with thrombotic anterior wall myocardial infarction 6 months after using a third generation low dose combined oral contraceptive pills (Marvelon; ethinylestradiol 30 mcg and desogestrel 150 mcg). CONCLUSION: Third generation low dose combined oral contraceptives may lead to myocardial infarction in young women, even in the absence of other cardiovascular risk factors.

Plasma concentrations of etonogestrel in women using oral desogestrel before and after Roux-en-Y gastric bypass surgery: a pharmacokinetic study.

OBJECTIVE: To investigate whether Roux-en-Y gastric bypass (RYGB) affects oral desogestrel (etonogestrel) pharmacokinetics. DESIGN: Single centre, open label, phase-2 pharmacokinetic study. SETTING: University hospital of Linköping, Sweden. POPULATION: Fourteen women with planned RYGB surgery were included; nine women aged 18-45 years using 75 micrograms desogestrel completed the study. METHODS: Steady-state etonogestrel pharmacokinetic (PK) parameters were measured on three occasions for each individual (at 8 ± 6 weeks before surgery, and at 12 ± 2 and 52 ± 2 weeks after surgery). Each patient served as her own control. On each occasion, serum samples were collected during a 24-hour period and etonogestrel concentrations were determined with ultra-performance liquid chromatography/tandem mass spectrometry. MAIN OUTCOME MEASURES: Area under the plasma concentration time curve of etonogestrel (AUC0-24 hours ). RESULTS: All women had significant postoperative weight loss. There were no significant differences in AUC0-24 hours , terminal half-lives (t½ ), time to peak serum concentrations (Tmax ), or apparent oral clearances of etonogestrel (CLoral ) before and after gastric bypass surgery on any occasion. Peak serum concentrations (Cmax ) increased after 52 ± 2 weeks compared with preoperative values (0.817 ng/ml versus 0.590 ng/ml, P = 0.024). CONCLUSION: To our knowledge, this is the first study to investigate the effects on desogestrel pharmacokinetics after RYGB. This study did not reveal any clinically significant changes in etonogestrel pharmacokinetics, suggesting that oral desogestrel may be used by women after RYGB surgery. The sample size was limited, however, and therefore the results should be interpreted cautiously. TWEETABLE ABSTRACT: The pharmacokinetics of oral desogestrel does not appear to change after gastric bypass surgery.

Norethindrone is superior to combined oral contraceptive pills in short-term delay of menses and onset of breakthrough bleeding: a randomized trial.

BACKGROUND: To determine whether oral norethindrone acetate is superior to combined oral contraceptives (OCP) in delaying menstruation and preventing breakthrough bleeding when started late in the cycle. METHODS: This article comprises of a case control study followed by a pilot randomized controlled study. In the first study, four women who presented late in their cycle and desired avoiding vaginal bleeding within 10 days before a wedding were started on norethindrone 5 mg three times daily and compared to age matched controls started on OCPs. Subsequently, a randomized controlled pilot study (n = 50) comparing OCPs to norethindrone for the retiming of menses was conducted. Percentage of women reporting spotting were compared with level of statistical significance set at p < 0.05. RESULTS: Of the norethindrone treated group, only 2 women (8%) reported spotting compared with 10 women (43%) in the control group (p < 0.01). Norethindrone recipients experienced significant weight gain, which resolved after cessation of therapy and had heavier withdrawal bleed (p < 0.04) when compared to controls. Patient satisfaction was significantly higher in the norethindrone group, with 80% willing to choose this method again. Time to conceive was significantly shorter in the norethindrone group (p < 0.03). CONCLUSIONS: Norethindrone, begun on or before cycle day 12, is superior for women who desire to avoid breakthrough bleeding and maintain fertility when compared to OCPs. It is an ideal approach in patients presenting late in their cycle and who desire delaying menses as well as in circumstances when even minute amounts of breakthrough bleeding cannot be tolerated. TRIAL REGISTRATION: Clinicaltrials.gov NCT03594604 , July 2018. Retrospectively registered.

Low-dose mifepristone increased angiogenesis in a manner involving AQP1.

PURPOSE: To investigate the molecular mechanisms governing aquaporin-1 (AQP1)-mediated, mifepristone-induced angiogenesis and improve the understanding of low-dose mifepristone serving as an anti-implantation contraceptive drug. METHODS: Human umbilical vein endothelial cells (HUVECs) were used to explore the effects of different concentrations of mifepristone (0, 65, and 200 nmol/L) on the activity of angiogenesis. Forty-five pregnant mice during the "window of implantation" were treated with different concentrations of mifepristone. HUVECs' proliferation was examined using a methyl thiazolyl tetrazolium (MTT) assay. The microvessel density (MVD) and the expression of AQP1 in endometrium were determined with immunohistochemical methods. RESULTS: The MVD and the expression of AQP1 were significantly higher than controls. Mifepristone at 200 nmol/L significantly affected HUVECs' proliferation during culture over 12 h, and pretreatment with AQP1-specific siRNA significantly inhibited the mifepristone-enhanced cell proliferation. CONCLUSIONS: Low-dose mifepristone increased angiogenesis in a manner involving AQP1. This affords a new insight into the molecular mechanism underpinning the angiogenic effects of low-dose mifepristone.

Preparation and Characterization of an Oral Norethindrone Sustained Release/Controlled Release Nanoparticles Formulation Based on Chitosan.

Norethindrone has short half-life and low bioavailability. The objective was to prepare an oral Sustained Release/Controlled Release (SR/CR) Liquid Medicated Formulation (LMF) to enhance bioavailability and improve patient compliance. Norethindrone was solubilized in HP-ß-CD then complexed with different concentrations of Low Molecular Weight Chitosan (LMWC) (mucoadhesive). PolyElectrolyte Complexes (PECs) were homogenized with oleic acid using different concentrations of tween 80 to form LMFs (nanoemulsions). PECs and LMFs were characterized using different techniques. LMF 2 (optimum formula containing 2.5% w/v LMWC 11 kDa) was administered orally to dogs and mice for pharmacokinetic and adhesion evaluation. DSC, FTIR spectroscopy and SEM images indicated complex formation. Mean diameters of PECs were 183-425 nm, mean zeta potentials were + 18.6-+ 31 mV, and complexation efficiencies were 18.0-20.6%. Ten to fifteen percent tween was needed to prepare homogenous LMFs. Mean diameter of LMF 2 was 10.5 ± 0.57 nm, mean zeta potential was - 11.07 ± - 0.49 mV, encapsulation efficiency was 95.28 ± 1.75%, and each mL contained 145.5 µg norethindrone. SEM images showed spherical homogeneous oil droplets. All of these parameters were affected by molecular weight and concentration of chitosan. Norethindrone release from LMFs was controlled (zero order) for 96 h. It was little affected by molecular weight and concentration of chitosan but affected by concentration of tween 80. LMF 2 adhered to GIT for 48 h and enhanced the bioavailability. It showed no cytotoxicity after considering dilution in GIT and was stable for 3 months refrigerated. In conclusion an effective SR/CR LMF was prepared.

Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study.

OBJECTIVE: Women with ovarian cancer have poor survival rates, which have proven difficult to improve; therefore primary prevention is important. The levonorgestrel-releasing intrauterine system (LNG-IUS) prevents endometrial cancer, and recent studies suggested that it may also prevent ovarian cancer, but with a concurrent increased risk of breast cancer. We compared adjusted risks of ovarian, endometrial, and breast cancer in ever users and never users of LNG-IUS. METHODS: Our study cohort consisted of 104,318 women from the Norwegian Women and Cancer Study, 9144 of whom were ever users and 95,174 of whom were never users of LNG-IUS. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated with Poisson regression using robust error estimates. RESULTS: Median age at inclusion was 52years and mean follow-up time was 12.5 (standard deviation 3.7) years, for a total of 1,305,435 person-years. Among ever users of LNG-IUS there were 18 cases of epithelial ovarian cancer, 15 cases of endometrial cancer, and 297 cases of breast cancer. When ever users were compared to never users of LNG-IUS, the multivariable RR of ovarian, endometrial, and breast cancer was 0.53 (95% CI: 0.32, 0.88), 0.22 (0.13, 0.40), and 1.03 (0.91, 1.17), respectively. CONCLUSION: In this population-based prospective cohort study, ever users of LNG-IUS had a strongly reduced risk of ovarian and endometrial cancer compared to never users, with no increased risk of breast cancer.

Effectiveness of the progestin-only pill for migraine treatment in women: A systematic review and meta-analysis.

Background Migraine is highly prevalent in women (18%). Peak morbidity affects their most productive years, coinciding with peak fertility. Hormonal contraception is often tailored for migraine prevention. Estrogen-containing contraceptives may be contraindicated in women experiencing migraine with aura due to the risk of vascular events. While improvements in migraine with a progestin-only pill (POP), which inhibits ovulation are documented, the strength and quality of evidence has not been formally evaluated. Objectives To determine the effectiveness of progestin-only contraceptives for migraine treatment by systematic review and meta-analysis. Data sources and selection MEDLINE, EMBASE and Cochrane Libraries were searched (1980 to September 2016) for studies on progestin-only treatments for migraine. Studies in English on >4 non-menopausal women aged 18-50 with migraine diagnosed by formal criteria were included. Data extraction and analysis Data were quality-assessed using the GRADE system. A random effects model was used for pooled analyses. Results Pooled analyses of four studies demonstrated that desogestrel 75 mcg/day, POP significantly but modestly reduced the number of migraine attacks and migraine days. Reduced intensity and duration, reduced analgesic and triptan use were observed, along with improved headache-related quality of life. GRADE analysis indicated evidence was low to very low for each outcome measure. Adverse effects resulted in treatment cessation for <10% of participants. Two studies compared desogestrel POP to a combined oral contraceptive, demonstrating similar migraine outcomes for both treatments. Conclusions The desogestrel POP shows promise in improving migraine in women. Current evidence is observational and based on small samples of women using only one oral progestin-only formulation. Further randomized trials on additional progestin-only contraceptives are required to confirm their role in migraine management.

Histopathologic Characterization of Mifepristone-induced Ovarian Toxicity in Cynomolgus Monkeys.

Mifepristone, which is an orally active synthetic steroid with antiprogesterone activity, is known as an ovarian toxicant. Because the available data regarding the histopathologic characteristics of ovarian toxicity in nonhuman primates are limited, the present study was undertaken in order to investigate detailed histopathologic changes accompanying mifepristone-induced ovarian toxicity and its relationship to changes in menstrual cycle and circulating sex steroid hormone. Twenty mg/kg of mifepristone was orally administered daily to 4 cynomolgus monkeys for 2 months. Mifepristone inhibited the cyclic increases in circulating estradiol-17ß and progesterone levels with associated absence of menstruation. Histopathologically, the ovary in the treated animals showed follicular phase without changes in the percentage of atretic antral follicles, and reduced endometrial thickness was noted in the uterus. These changes indicated that a certain degree of antral follicle development had been retained in spite of the menstrual cycle having been arrested in mifepristone-treated animals. Our investigation suggested that it is important to perform detailed histopathologic examination of reproductive organs with precise knowledge of the characteristics of each menstrual stage to detect ovarian toxicity in nonhuman primates. Monitoring menstrual signs and circulating sex steroid hormone levels provides additional evidence for the investigation of the mechanism of ovarian toxicity.

Pericoital contraception.

PURPOSE OF REVIEW: To evaluate the literature on repeat use of emergency contraception and pericoital approaches to contraception. RECENT FINDINGS: Women are very interested in an oral, on-demand contraceptive option, were one available. Ulipristal acetate and a combination of levonorgestrel (LNG) and meloxicam (a cyclo-oxygenase-2 inhibitor) both appear to be more effective at disrupting ovulation than LNG alone. Recent advisories from the United Kingdom regarding daily dosing of ulipristal for fibroids emphasize the need for more safety data. SUMMARY: Repeat pericoital dosing of 1.5-mg LNG is approximately as effective as other on-demand contraceptive methods and is overall very safe. The most common side effect is irregular bleeding. Repeat on-demand ulipristal acetate or meloxicam/other cyclo-oxygenase-2 inhibitors have potential as an on-demand option either alone or in combination but have not been evaluated for contraceptive efficacy in a large-scale study. Given the high unmet need for contraception, even among women with access to available options, there is a distinct need for options that address needs of women who are interested in an on-demand option. On-demand oral contraception has the potential to expand the convenience of contraceptive options and overall contraceptive use.

Discontinuation rate of Implanon and its associated factors among women who ever used Implanon in Dale District, Southern Ethiopia.

BACKGROUND: Early discontinuation of the Implanon contraceptive method and reasons for such discontinuation remains a major concern for family planning programs. In less developed countries, contraceptive discontinuation due to health concerns is generally higher, these complaints are often related to service quality. Significant numbers of women become exposed to conception after discontinuation and accidental pregnancies that end up with abortion & stillbirth. The aim of this study was to assess the early discontinuation rate of Implanon and identify its associated factors among women who ever used Implanon in 2016 in Dale district, Southern Ethiopia. METHODS: Community based cross-sectional study design was conducted from January to February, 2017. A total number of 711 women who ever used Implanon in 2016 were selected using multistage sampling. The data were entered and cleaned in Epi Info and analyzed using SPSS. Multivariate logistic regression analysis was used to determine the effect of factors on the outcome variables. Finally, the results were presented using adjusted odds ratio (AOR) & confidence interval of 95%. RESULT: Early Implanon discontinuation rate in this study was 160 (23.4%) with a mean duration of Implanon use of 9.6 ± 2.5 months. The main reasons for discontinuation of Implanon were 55 (34.4%) the facing of side effects. Factors for discontinuation of Implanon were women age 20-24 years (AOR =. 44 (95% CI: 23-. 85), 25-29 years (AOR =. 52 (95% CI: 27-. 96), 35+ years, (AOR =. 08 (95% CI: 02-. 41), less likely to discontinue. Women who weren't counseled about the side effects during Implanon insertion were 1.93 times (AOR = 1.93 (95% CI: 1.27-2.93), women who didn't satisfied by the service (AOR = 2.55(CI: 95%: 1.63-3.97), women who didn't appointed for follow up (AOR = 3.13 (CI: 95%: 2.0-4.95), women who didn't choose the method by themselves (AOR = 1.83 (CI: 95%: 1.18-2.83) and women who didn't have information on family planning before Implanon insertion (AOR = 1.52 (CI: 95%: 1.1-2.28) were the predictors of Implanon discontinuation. CONCLUSIONS: Implanon discontinuation rate in this study area was high. Appropriate counseling prior to insertion and proper follow up, autonomous choice will improve the continuation rate of Implanon.

Acute pancreatitis secondary to oral contraceptive-induced hypertriglyceridemia: a case report.

Hypertriglyceridemia is the third most common cause of acute pancreatitis. Among the causes that lead to secondary hypertriglyceridemia, the use of contraceptive agents is the main reason to be assessed in young women. We report a case of a 31-year-old woman who had suffered two acute pancreatitis episodes secondary to hypertriglyceridemia. In the investigation, the previous medical team indicated a genetic screening before ruling out all secondary causes. LPL, apo CII and apo AV genes were negative for mutations. In the first appointment with us, the patient reported the use of a contraceptive agent for about 2 years. She was instructed to discontinue the drug. After one year of follow-up, her serum triglycerides are within the normal range and a copper intrauterine device was the method chosen by the patient for contraception.

Shifting from Oral Contraceptives to Norethisterone Acetate, or Vice Versa, because of Drug Intolerance: Does the Change Benefit Women with Endometriosis?

BACKGROUND/AIMS: Oral contraceptives (OC) and norethisterone acetate (NETA) are among first-line medical therapies for symptomatic endometriosis, but their use is sometimes associated with intolerable side effects. We investigated whether shifting from low-dose OC to NETA (2.5 mg/day), or vice versa, improved tolerability. METHODS: Sixty-seven women willing to discontinue their treatment because of intolerable side effects despite good pain relief, were enrolled in a self-controlled study, and shifted from OC to NETA (n = 35) or from NETA to OC (n = 32). The main study outcome was satisfaction with treatment 12 months after the change. Tolerability, pain symptoms, health-related quality of life, psychological status, and sexual functioning were also evaluated. RESULTS: After treatment change, good tolerability was reported by 37% of participants who shifted to NETA, and by 52% of those who shifted to OC. At 12-month assessment, 51% of women intolerant to OC were satisfied with NETA, and 65% of those intolerant to NETA were satisfied with OC (intention-to-treat analysis). Other study variables did not vary substantially. CONCLUSIONS: In selected endometriosis patients, shifting from OC to NETA, or vice versa, because of side effects, improved tolerability. Better results were observed when substituting NETA with OC rather than the other way round.

Metabolite Identification, Reaction Phenotyping, and Retrospective Drug-Drug Interaction Predictions of 17-Deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate.

Ortho Tri-Cyclen, a two-drug cocktail comprised of ethinylestradiol and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported. Hence, detailed biotransformation and reaction phenotyping studies of NGMN with recombinant cytochrome P450 (P450), recombinant uridine 5'-diphospho-glucuronosyltransferases, and human liver microsomes in the presence and absence of selective P450 inhibitors were conducted. It was found that CYP3A4 plays a key role in NGMN metabolism with a fraction metabolized (fm) of 0.57. CYP2B6 and to an even lesser extent CYP2C9 were also observed to catalyze NGMN metabolism. Using this CYP3A4 fm value, the predicted plasma concentration versus time area under the curve (AUC) change in NGMN using a basic/mechanistic static model was found to be within 1.3-fold of the reported NGMN AUC changes for four modulators of CYP3A4. In addition to NGMN, we have also elucidated the biotransformation of norgestrel (NG), a downstream norgestimate and NGMN metabolite, and found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combined fm value of 1. The data presented in this paper will lead to better understanding and management of NGMN-based drug-drug interactions when norgestimate is coadministered with CYP3A4 modulators.

Postoperative maintenance levonorgestrel-releasing intrauterine system and endometrioma recurrence: a randomized controlled study.

BACKGROUND: According to 3 randomized trials, the levonorgestrel-releasing intrauterine system significantly reduced recurrent endometriosis-related pelvic pain at postoperative year 1. Only a few studies have evaluated the long-term effectiveness of the device for preventing endometrioma recurrence, and the effects of a levonorgestrel-releasing intrauterine system as a maintenance therapy remain unclear. OBJECTIVE: The objective of the study was to evaluate whether a maintenance levonorgestrel-releasing intrauterine system is effective for preventing postoperative endometrioma recurrence. STUDY DESIGN: From May 2011 through March 2012, a randomized controlled trial including 80 patients with endometriomas undergoing laparoscopic cystectomy followed by six cycles of gonadotropin-releasing hormone agonist treatment was conducted. After surgery, the patients were randomized to groups that did or did not receive a levonorgestrel-releasing intrauterine system (intervention group, n = 40, vs control group, n = 40). The primary outcome was endometrioma recurrence 30 months after surgery. The secondary outcomes included dysmenorrhea, CA125 levels, noncyclic pelvic pain, and side effects. RESULTS: Endometrioma recurrence at 30 months did not significantly differ between the 2 groups (the intervention group, 10 of 40, 25% vs the control group 15 of 40, 37.5%; hazard ratio, 0.60, 95% confidence interval, 0.27-1.33, P = .209). The intervention group exhibited a lower dysmenorrhea recurrence rate, with an estimated hazard ratio of 0.32 (95% confidence interval, 0.12-0.83, P = .019). Over a 30 month follow-up, the intervention group exhibited a greater reduction in dysmenorrhea as assessed with a visual analog scale score (mean ± SD, 60.8 ± 25.5 vs 38.7 ± 25.9, P < .001, 95% confidence interval, 10.7-33.5), noncyclic pelvic pain visual analog scale score (39.1 ± 10.9 vs 30.1 ± 14.7, P = .014, 95% confidence interval, 1.9-16.1), and CA125 (median [interquartile range], -32.1 [-59.1 to 14.9], vs -15.6 [-33.0 to 5.0], P = .001) compared with the control group. The number-needed-to-treat benefit for dysmenorrhea recurrence at 30 months was 5. The number of recurrent cases requiring further surgical or hormone treatment in the intervention group (1 of 40, 2.5%, 95% confidence interval, -2.3% to 7.3%) was significantly lower than that in the control group (8 of 40, 20%, 95% confidence interval, 7.6-32.4%; P = .031). CONCLUSION: Long-term maintenance therapy using a levonorgestrel-releasing intrauterine system is not effective for preventing endometrioma recurrence.

Contraceptive use in the Nordic countries.

INTRODUCTION: The aim was to compare contraceptive use in the Nordic countries and to assess compliance with recommendations from the European Medicines Agency regarding the use of combined oral contraception containing low-dose estrogen and levonorgestrel, norethisterone or norgestimate. MATERIAL AND METHODS: Data on hormonal contraceptive prescriptions and sales figures for copper intrauterine devices were obtained from national databases and manufacturers in Denmark, Finland, Iceland, Norway and Sweden in 2010-2013. RESULTS: Contraceptive use was highest in Denmark (42%) and Sweden (41%), followed by Finland (40%). Combined oral contraception was the most used method in all countries, with the highest use in Denmark (26%). The second most used method was the levonorgestrel-releasing intrauterine system, with the highest use in Finland (15%) and ≈10% in the other countries. Copper intrauterine devices (7%) and the progestin-only pill (7%) were most often used in Sweden. Combined oral contraception use decreased with increasing age and levonorgestrel-releasing intrauterine system and progestin-only pills use increased. The use of long-acting reversible methods of contraception (=levonorgestrel-releasing intrauterine system, copper intrauterine devices, and implants) increased with time and was highest in Sweden (20%) and Finland (18%). The highest use of European Medicines Agency recommended combined oral contraception was in Denmark, increasing from 13 to 50% between 2010 and 2013. In Finland, recommended combined oral contraception remained below 1%. CONCLUSIONS: Contraceptive use was highest in Denmark and Sweden, levonorgestrel-releasing intrauterine system use was highest in Finland and all long-acting methods were most common in Sweden. The use of combined oral contraception recommended by the European Medicines Agency was highest in Denmark.

Hormonal contraception: venous and arterial disease.

OBJECTIVES: The aim of this review was to evaluate whether the biological and epidemiological evidence is concordant in suggesting that levonorgestrel (LNG)-based hormonal contraceptives (HCs) are safer than newer formulations with regard to their effect on the cardiovascular system. METHODS: A narrative review was carried out of the modification of risk factors for venous thromboembolism (VTE) and arterial diseases induced by different HCs. Limits and concordance with epidemiological data were addressed. RESULTS: The data indicate general concordance between modifications of risk factors and epidemiology of VTE, with LNG-based HCs showing lower risk compared with most new formulations. Evidence for drospirenone (DRSP)-containing HCs is conflicting. LNG-based HCs are less favourable than HCs containing non-androgenic progestins, particularly DRSP, on risk factors for arterial events. Epidemiological studies do not consistently show a difference in arterial disease outcomes between different HCs; however, by evaluating women up to the age of 50, they do not take into consideration the time lag necessary for atherosclerosis to develop. CONCLUSIONS: As a consequence of the different risk factors involved, and the different time lags between HC use and the manifestation of VTE or arterial diseases, the available epidemiological data do not give a reliable estimate of the cardiovascular risk associated with the use of different HCs. LNG-based HCs are safer than newer HCs as regards VTE risk, but biological data indicate that they are less favourable, particularly than HCs containing DRSP, on risk factors for atherosclerosis. Because of the limits of actual epidemiological evidence regarding arterial disease, modifications of arterial risk factors should be taken into consideration when considering individual long-term safety of HC use.

The effect of chlormadinone acetate on odontogenic differentiation of human dental pulp cells: in vitro study.

BACKGROUND: Chlormadinone acetate (CMA) is a derivative of progesterone and is used as an oral contraceptive. The aim of this study was to investigate the effects of CMA on odontogenic differentiation and mineralization of human dental pulp cells (hDPCs) and related signaling pathways. METHODS: Cell viability was determined by the water-soluble tetrazolium (WST)-1 assay. Odontogenic differentiation of hDPCs was evaluated by real-time polymerase chain reaction using odontogenic marker genes, such as alkaline phosphatase (ALP), osteocalcin (OCN), dentin sialophosphoprotein (DSPP), and dentin matrix protein-1 (DMP-1). Mineralization of hDPCs was evaluated by ALP staining and alizarin red staining. The extracellular signal-regulated kinase (ERK) pathway was examined by Western blot analysis. RESULTS: There was no statistically significant difference in cell viability between the control and CMA-treated groups. Our analysis of odontogenic marker genes indicated that CMA enhanced the expression of those genes. CMA-treated hDPCs showed increased ALP activity and formation of mineralized nodules, compared with control-treated cells. In addition, CMA stimulation resulted in phosphorylation of ERK and resulted in inhibition of downstream molecules by the ERK inhibitor U0126. CONCLUSIONS: These findings suggest that CMA improves odontogenic differentiation and mineralization of hDPCs through the ERK signaling pathway.

Clinical efficacy of levonorgestrel and norethisterone for the treatment of chronic abnormal uterine bleeding.

OBJECTIVE: To compare the clinical efficacy of levonorgestrel intrauterine system with oral norethisterone for the treatment of idiopathic chronic abnormal uterine bleeding. METHODS: This cross-sectional study was conducted at Bahawal Victoria Hospital, Jubilee Female Hospital, Civil Hospital and private clinics of consultant gynaecologists in Bahawalpur, Pakistan, from March to August 2014, and comprised patients presenting with abnormal uterine bleeding. The patients were equally and randomly divided into two groups, i.e. intrauterine levonorgestrel administered (group A) and norethisterone administered (group B). Mean age, duration of the disease and parity were determined using a predesigned questionnaire. The primary outcomes of the treatments, i.e. reduction in menstrual blood loss assessed by the pictorial blood assessment chart score, were recorded before the initiation of therapy, at 3 months and at 6months of the study. SPSS 16 was used for data analysis. RESULTS: There were 76 subjects; 38(50%) in each group. In group A, the mean age and mean duration of the disease was 34.16±6.327 years and 6.18±2.415 years compared to 34.21±3.595 years and 6.21±2.418 years in group B. The reduction in menstrual blood loss did not differ significantly between the groups after 3 months (p= 0.321). However, levonorgestrel intrauterine system was found more effective in reducing menstrual blood loss in 36(94.73%) patients, compared to norethisterone-treated patients 28(73.68%) after 6 months of the treatment (p=0.041). The response of both the treatments was found independent of patient's age, parity and chronicity of the disease. CONCLUSIONS: The levonorgestrel intrauterine system was better than norethisterone with marked clinical benefit of profound reduction in menstrual blood loss.