The effect of a combined indomethacin and levonorgestrel-releasing intrauterine system on short-term postplacement bleeding profile: a randomized proof-of-concept trial.

BACKGROUND: Long-acting reversible contraceptives, including hormonal levonorgestrel-releasing intrauterine systems, are the most effective methods of reversible contraception. However, unfavorable bleeding, particularly during the first months of use, is one of the most important reasons for discontinuation or avoidance. Minimizing this as early as possible would be highly beneficial. Nonsteroidal anti-inflammatory drugs inhibiting prostaglandin synthesis are known to reduce bleeding and pain at time of menses. A levonorgestrel-releasing intrauterine system has been developed with an additional reservoir containing indomethacin, designed to be released during the initial postplacement period. OBJECTIVE: This proof-of-concept study aimed to establish whether the addition of indomethacin to the currently available levonorgestrel-releasing intrauterine system (average in vivo levonorgestrel release rate of 8 µg/24 h during the first year of use) reduces the number of bleeding and spotting days during the first 90 days of use compared with the unmodified system. The dose-finding analysis included 3 doses of indomethacin-low (6.5 mg), middle (12.5 mg), and high (15.4 mg)-to determine the ideal dose of indomethacin to reduce bleeding and spotting days with minimal side-effects. STUDY DESIGN: This was a multicenter, single-blinded, randomized, controlled phase II trial conducted between June 2018 and June 2019 at 6 centers in Europe. Three indomethacin dose-ranging treatment groups (low-, middle-, and high-dose indomethacin/levonorgestrel-releasing intrauterine system) were compared with the unmodified levonorgestrel-releasing intrauterine system group, with participants randomized in a 1:1:1:1 ratio. The primary outcome was the number of uterine bleeding and spotting days over a 90-day reference (treatment) period. Secondary outcomes were the number of women showing endometrial histology expected for intrauterine levonorgestrel application and the frequency of treatment-emergent adverse events. Point estimates and 2-sided 90% credible intervals were calculated for mean and median differences between treatment groups and the levonorgestrel-releasing intrauterine system without indomethacin. Point and interval estimates were determined using a Bayesian analysis. RESULTS: A total of 174 healthy, premenopausal women, aged 18 to 45 years, were randomized, with 160 women eligible for the per-protocol analysis set. Fewer bleeding and spotting days were observed in the 90-day reference period for the 3 indomethacin/levonorgestrel-releasing intrauterine system dose groups than for the levonorgestrel-releasing intrauterine system without indomethacin group. The largest reduction in bleeding and spotting days was achieved with low-dose indomethacin/levonorgestrel-releasing intrauterine system, which demonstrated a point estimate difference of -32% (90% credible interval, -45% to -19%) compared with levonorgestrel-releasing intrauterine system without indomethacin. Differences for high- and middle-dose indomethacin/levonorgestrel-releasing intrauterine system groups relative to levonorgestrel-releasing intrauterine system without indomethacin were -19% and -16%, respectively. Overall, 97 women (58.1%) experienced a treatment-emergent adverse event considered related to the study drug, with similar incidence across all treatment groups including the unmodified levonorgestrel-releasing intrauterine system. These were all mild or moderate in intensity, with 6 leading to discontinuation. Endometrial biopsy findings were consistent with effects expected for the levonorgestrel-releasing intrauterine system. CONCLUSION: All 3 doses of indomethacin substantially reduced the number of bleeding and spotting days in the first 90 days after placement of the levonorgestrel-releasing intrauterine system, thus providing proof of concept. Adding indomethacin to the levonorgestrel-releasing intrauterine system can reduce the number of bleeding and spotting days in the initial 90 days postplacement, without affecting the safety profile, and potentially improving patient acceptability and satisfaction.

Practical training of health care providers in insertion of contraceptive implants: findings from two Brazilian centres.

BACKGROUND AND OBJECTIVES: Lack of information and myths or inadequate training of health care providers in the guidance and management of contraceptives could negatively affect choice and eventually continuation rates. Our objectives were to evaluate the impact of clinical and theoretical training of health care professionals on insertion and removal of etonogestrel (ENG)-implant regarding this contraceptive, including pre- and post-training knowledge about insertion and removal techniques, clinical characteristics, side effects and outcomes. MATERIAL AND METHODS: We conducted a cross-sectional study in which a questionnaire was sent to health care providers after they received clinical training in the management of ENG-implant. RESULTS: After training, 78.2% of the 139 participants initiated to offer and inserted up to 5 implants/month and 17.6% between 6 to 10/month. None of the interviewees reported having difficulty with insertions after training, and 87.9% reported feeling very confident for removal. CONCLUSION: Theoretical and practical training appeared important to prepare health care professionals, clarify doubts and promote higher rates of use of contraceptive implants in Brazil, contributing to reduce the rates of unintended pregnancies.

Gene expression profiling of Trypanosoma cruzi in the presence of heme points to glycosomal metabolic adaptation of epimastigotes inside the vector.

Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite, Trypanosoma cruzi, and is transmitted by triatomine insects during its blood meal. Proliferative epimastigotes forms thrive inside the insects in the presence of heme (iron protoporphyrin IX), an abundant product of blood digestion, however little is known about the metabolic outcome of this signaling molecule in the parasite. Trypanosomatids exhibit unusual gene transcription employing a polycistronic transcription mechanism through trans-splicing that regulates its life cycle. Using the Deep Seq transcriptome sequencing we characterized the heme induced transcriptome of epimastigotes and determined that most of the upregulated genes were related to glucose metabolism inside the glycosomes. These results were supported by the upregulation of glycosomal isoforms of PEPCK and fumarate reductase of heme-treated parasites, implying that the fermentation process was favored. Moreover, the downregulation of mitochondrial gene enzymes in the presence of heme also supported the hypothesis that heme shifts the parasite glycosomal glucose metabolism towards aerobic fermentation. These results are examples of the environmental metabolic plasticity inside the vector supporting ATP production, promoting epimastigotes proliferation and survival.

Effect of the levonorgestrel-releasing intrauterine system on cardiovascular risk markers among women with thrombophilia or previous venous thromboembolism.

OBJECTIVE: To assess the effects of the levonorgestrel-releasing intrauterine system (LNG-IUS) on standard cardiovascular risk markers among women with thrombophilia and/or previous venous thromboembolism (VTE). METHODS: A prospective cohort study enrolled women aged 18-45 years with thrombophilia and/or a history of VTE who received the 52-mg LNG-IUS (20 µg/d initial release) at the University of Ribeirão Preto Medical School, Brazil, from January 2006 to December 2015. Before and 12 months after LNG-IUS placement, the following cardiovascular risk markers were assessed: lipid profile, body mass index (BMI), blood glucose, systolic blood pressure, diastolic blood pressure, and waist circumference. The primary outcome was changes in cardiovascular risk markers. A subanalysis of anticoagulant users versus non-users was also conducted. RESULTS: In total, 45 women were enrolled. BMI increased by 2.3% after 12 months of LNG-IUS placement (P < 0.01), but the other risk factors did not change. Cardiovascular risk markers were similar between anticoagulant users and non-users after 12 months of LNG-IUS use. CONCLUSION: Among women with thrombophilia and/or previous VTE, cardiovascular risk markers were not found to change significantly after 12 months of LNG-IUS use. The study adds safety information regarding use of the LNG-IUS for women at risk of thromboembolism.

Can initial vaginal bleeding patterns in etonogestrel implant users predict subsequent bleeding in the first 2 years of use?

OBJECTIVES: To evaluate if a simple method for characterizing vaginal bleeding patterns in etonogestrel contraceptive implant users can predict subsequent patterns and bleeding-related discontinuation over the first 2 years of use. STUDY DESIGN: We reanalyzed phase 3 study bleeding data for non-breastfeeding participants from the United States, Europe, Russia and Chile during the first 2 years of implant use to characterize and correlate bleeding patterns. We used 90-day reference periods with period 1.1 starting at Day 29 and ending at Day 118. We dichotomized bleeding patterns as "favorable" (amenorrhea, infrequent bleeding and normal frequency bleeding without prolonged bleeding) or "unfavorable' (prolonged and/or frequent bleeding) and tracked user groups based on these bleeding patterns in reference period 1.1 through Year 1 and from Year 1 through Year 2, respectively. RESULTS: We evaluated data from 537 and 428 women with up to 1 and 2 years use, respectively. Of the 325 (60.5%) women with favorable bleeding in reference period 1.1, 275 (84.6%) reported favorable bleeding also in reference period 2, 197 (60.6%) reported favorable bleeding throughout Year 1, and favorable bleeding in 75-85% of reference periods in Year 2. Among 212 (39.5%) women with unfavorable bleeding in reference period 1.1, 118 (55.7%) continued with unfavorable bleeding in reference period 2, while about 40%-50% reported favorable patterns in RP 2, 3 and/or 4. Initial favorable bleeding resulted in lower discontinuation rates than initial unfavorable bleeding in years 1 (3.7% vs 12.7%, p≪.0001) and 2 (2.5% vs 16.5%, p≪.0001). CONCLUSION: Implant users with favorable bleeding in the first reference period are likely to continue with favorable bleeding over the next 2 years. Initial bleeding patterns predict overall continuation rates in years 1 and 2. Implications Statement When evaluating vaginal bleeding in any 90-day reference period over 2 years of etonogestrel implant use, approximately 80% of women with favorable and 40% with unfavorable bleeding patterns will have favorable bleeding in the next reference periods. These findings can facilitate counseling regarding bleeding for women using the etonogestrel implant.

Safety of hormonal contraception for obese women.

INTRODUCTION: Obese women have special safety requirements for contraceptive choice, but the evidence supporting such decision is dispersed and sometimes conflicting. Despite being effective, well tolerated and safe for most women, hormonal contraceptives are underused by obese women due to fear of contraceptive failure, weight gain and venous thrombosis. Areas covered: We performed a comprehensive literature search to identify studies about hormonal contraception in overweight and obese women, including safety concerns. We considered the safety of hormonal contraceptives for otherwise healthy obese women and for those with comorbidities such as hypertension, diabetes, vascular disease, or a history of deep venous thrombosis. Expert opinion: Over time there is no convincing evidence that obesity increases the risk of contraceptive failure. Hormonal contraceptive users may have a modest weight gain that is comparable to that of non-users. Current evidence supports the safe use of combined hormonal contraceptives by obese women after detailed clinical screening to exclude comorbidities that may contraindicate the use of estrogens. Progestin-only methods are generally safe, and long-acting reversible contraceptives hold the best combination of efficacy, safety and convenience for this group, although individualization is advisable.

Cardiovascular risk markers among obese women using the levonorgestrel-releasing intrauterine system: A randomised controlled trial.

According to international guidelines, women with obesity without other comorbidities can safely use any hormonal contraceptive (HC). However, limited information is available about contraceptive safety for women with obesity since obesity is an exclusion criterion of most contraceptive clinical trials. As such little is known about the possible risks of HC exposure for women with obesity without comorbidities. One way to assess possible long-term risks in this population, even prior to the development of any clinical disease, is to measure alterations in subclinical atherosclerosis markers. We evaluated the effects of the levonorgestrel-releasing intrauterine system (LNG-IUS) on subclinical markers of cardiovascular risk in women with obesity. This is a randomised clinical trial in which 106 women with obesity [body mass index (BMI)≥30kg/m2] were randomised to the LNG-IUS (n=53) or to non-hormonal methods (n=53) and followed for 12 months. We evaluated waist circumference (WC), blood pressure, blood glucose, insulin, lipid profile, and endothelial function markers (carotid intima-media thickness, brachial artery flow-mediated dilation, and carotid arterial stiffness). At 12 months, BMI (p=0.005), WC (p=0.045), and glucose levels (p=0.015) were significantly lower in the LNG-IUS group than in the control group. We did not find any clinically relevant changes in subclinical markers of cardiovascular risk among with obesity women at 12 months after LNG-IUS placement compared to users of non-hormonal contraceptive methods.

Neurologist knowledge about interactions between antiepileptic drugs and contraceptive methods.

OBJECTIVE: To evaluate neurologists' knowledge of contraceptive counseling for women receiving antiepileptic drugs (AEDs). METHODS: An interview-based survey was conducted from February 2 to June 30, 2015, among neurologists working in Ribeirão Preto, Brazil. Direct interviews were conducted using a questionnaire that assessed knowledge of the pharmacological interactions between various contraceptive methods and six AEDs (carbamazepine, phenobarbital, topiramate, phenytoin, lamotrigine, and valproate) on the basis of WHO medical eligibility criteria for contraceptive use. RESULTS: Among 42 neurologists who participated, 32 (76%) stated that they treated women with epilepsy and provided them with counseling for family planning. Overall, 34 (81%) recommended the use of a copper intrauterine device irrespective of the AED used, and 26 (60%) stated that they co-prescribed AEDs and hormonal contraceptives. Although 39 (93%) neurologists had knowledge that AEDs might contraindicate the use of some contraceptives, their knowledge regarding the specific drug interactions was lacking. Furthermore, 34 (81%) had no knowledge of WHO medical eligibility criteria for contraceptive use. CONCLUSION: Although most neurologists interviewed had knowledge of interactions between AEDs and hormonal contraceptives, they did not know which specific AEDs interacted with these agents.

Effects of two contraceptives containing drospirenone on blood pressure in normotensive women: a randomized-controlled trial.

OBJECTIVE: Drospirenone (DRSP) is a progestogen derived from spironolactone with antimineralocorticoid action that seems to exert a favorable effect on blood pressure (BP); however, when associated with ethinylestradiol (EE), this effect does not seem to occur. This study aimed to assess possible differences in BP associated with the use of combined oral contraceptives containing DRSP with different doses of EE. MATERIALS AND METHODS: This open-label parallel-group randomized clinical trial involved women randomized to use either 30 mcg of EE+DRSP (n=22) or 20 mcg of EE+DRSP (n=22). Daytime, nighttime, and 24-h BP were evaluated by ambulatory blood pressure monitoring at the beginning of the trial and 6 months after drug therapy. RESULTS: The groups were similar in terms of demographic characteristics. The mean 24-h systolic blood pressure and diastolic blood pressure (DBP) were similar between the groups before and after treatment (P>0.05). With respect to day and nighttime systolic blood pressure and DBP, no statistically significant difference was observed in BP values between the two groups either before or after treatment, except for the daytime DBP in the 30EE+DRSP group. In this group, a decrease of 2 mmHg (3%) in daytime DBP was observed after 6 months of drug therapy (P=0.04). CONCLUSION: There was no difference in BP associated with the use of combined oral contraceptives containing DRSP irrespective of the EE dose used.

Add-back therapy with GnRH analogues for uterine fibroids.

BACKGROUND: Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms such as bleeding and pain. Medical treatment of this condition is limited and gonadotropin-releasing hormone (GnRH) analogues are the most effective agents. Long-term treatment with such agents, however, is restricted due to their adverse effects. The addition of other medications during treatment with GnRH analogues, a strategy known as add-back therapy, may limit these side effects. There is concern, however, that add-back therapy may also limit the efficacy of the GnRH analogues and that it may not be able to completely prevent their adverse effects. OBJECTIVES: To assess the short-term (within 12 months) effectiveness and safety of add-back therapy for women using GnRH analogues for uterine fibroids associated with excessive uterine bleeding, pelvic pain, or urinary symptoms. SEARCH METHODS: We searched electronic databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, LILACS, CINAHL, PsycINFO; and electronic registries of ongoing trials including ClinicalTrials.gov, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform. All searches were from database inception to 16 June 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) that included women with uterine fibroids experiencing irregular or intense uterine bleeding, cyclic or non-cyclic pelvic pain, or urinary symptoms, and that compared treatment with a GnRH analogue plus add-back therapy versus a GnRH analogue alone or combined with placebo were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the identified titles and abstracts for potentially eligible records. Two review authors reviewed eligible studies and independently extracted data. Two authors independently assessed the studies' risk of bias. They assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: Fourteen RCTs were included in the review. Data were extracted from 12 studies (622 women). The primary outcome was quality of life (QoL).Add-back therapy with medroxyprogesterone (MPA): no studies reported QoL or uterine bleeding. There was no evidence of effect in relation to bone mass (standardized mean difference (SMD) 0.38, 95% confidence interval (CI) -0.62 to 1.38, 1 study, 16 women, P = 0.45, low quality evidence) and MPA was associated with a larger uterine volume (mean difference (MD) 342.19 cm(3), 95% CI 77.58 to 606.80, 2 studies, 32 women, I(2) = 0%, low quality evidence).Tibolone: this was associated with a higher QoL but the estimate was imprecise and the effect could be clinically insignificant, small or large (SMD 0.47, 95% CI 0.09 to 0.85, 1 study, 110 women, P = 0.02, low quality evidence). It was also associated with a decreased loss of bone mass, which could be insignificant, small or moderate (SMD 0.36, 95% CI 0.03 to 0.7, 3 studies, 160 women, I(2) = 7%, moderate quality evidence). Tibolone may, however, have been associated with larger uterine volumes (MD 23.89 cm(3), 95% CI= 8.13 to 39.66, 6 studies, 365 women, I(2) = 0%, moderate quality evidence) and more uterine bleeding (results were not combined but three studies demonstrated greater bleeding with tibolone while two other studies demonstrated no bleeding in either group). Four studies (268 women; not pooled owing to extreme heterogeneity) reported a large benefit on vasomotor symptoms in the tibolone group.Raloxifene: there was no evidence of an effect on QoL (SMD 0.11, 95% CI -0.57 to 0.34, 1 study, 74 women, P = 0.62, low quality evidence), while there was a beneficial impact on bone mass (SMD 1.01, 95% CI 0.57 to 1.45, 1 study, 91 women, P < 0.00001, low quality evidence). There was no clear evidence of effect on uterine volume (MD 27.1 cm(3), 95% CI -17.94 to 72.14, 1 study, 91 women, P = 0.24, low quality evidence), uterine bleeding or severity of vasomotor symptoms (MD 0.2 hot flushes/day, 95% CI -0.34 to 0.74, 1 study, 91 women, P = 0.46, low quality evidence).Estriol: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. Add-back with estriol may have led to decreased loss of bone mass, from results of a single study (SMD 3.93, 95% CI 1.7 to 6.16, 1 study, 12 women, P = 0.0005, low quality evidence).Ipriflavone: no studies reported QoL, uterine size or uterine bleeding. Iproflavone was associated with decreased loss of bone mass in a single study (SMD 2.71, 95% CI 2.14 to 3.27, 1 study, 95 women, P < 0.00001, low quality evidence); there was no evidence of an effect on the rate of vasomotor symptoms (RR 0.67, 95% Cl 0.44 to 1.02, 1 study, 95 women, P = 0.06, low quality evidence).Conjugated estrogens: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. One study suggested that adding conjugated estrogens to GnRH analogues resulted in a larger decrease in uterine volume in the placebo group (MD 105.2 cm(3), 95% CI 27.65 to 182.75, 1 study, 27 women, P = 0.008, very low quality evidence).Nine of 12 studies were at high risk of bias in at least one domain, most commonly lack of blinding. All studies followed participants for a maximum of six months. This short-term follow-up is usually insufficient to observe any significant effect of the treatment on bone health (such as the occurrence of fractures), limiting the findings. AUTHORS' CONCLUSIONS: There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive.

Combined oral contraceptive for treatment of women with uterine fibroids and abnormal uterine bleeding: a systematic review.

BACKGROUND/AIMS: We aimed at assessing the efficacy of combined oral contraceptives (COC) in treating women with uterine leiomyomata and heavy menstrual bleeding (HMB), as well as their effect over quality of life (QoL), tumor size, and hemoglobin concentration. METHODS: We searched various electronic databases and reference lists from all included studies. Randomized and nonrandomized controlled clinical trials were selected, and two trials were considered eligible - one randomized and one 'pseudo'-randomized. RESULTS: COCs performed less well than levonorgestrel-releasing intrauterine systems (LNG-IUSs) in controlling HMB, improving QoL, and improving the hemoglobin concentration, whereas the estimate was not sufficiently precise to define whether COCs were better than, equal to, or worse than LNG-IUSs in reducing tumor size. It must be stressed that these results are based on low-quality evidence, stemming from a single trial. Additionally, COCs were more effective than placebo in tumor size reduction, another conclusion based on another single study, considered as being at a high risk of bias and judged as very low-quality evidence. CONCLUSION: Evidence regarding the use of COCs as treatment for women with symptomatic fibroids is very scarce and of low quality, and we are very uncertain about the real efficacy of such treatment.

Comparison of the hemostatic effects of a levonorgestrel-releasing intrauterine system and leuprolide acetate in women with endometriosis: a randomized clinical trial.

INTRODUCTION: The hemostatic and inflammatory systems may activate each other. Endometriosis is a chronic inflammatory disease affecting 10% of women. The objective of this study was to compare the hemostatic effects of two treatments widely prescribed to women with endometriosis: the levonorgestrel intrauterine system (LNG-IUS) and the gonadotropin-releasing hormone analog (GnRHa) leuprolide acetate. MATERIALS AND METHODS: In this randomized open-label controlled trial, 44 women with endometriosis were randomly allocated to one of two groups: 22 women were assigned to use LNG-IUS and 22 to use GnRHa. The assessed variables were D-dimers, fibrinogen, prothrombin time, activated partial thromboplastin time, coagulation factors (F) II, V, VII, VIII, IX, X, and XI, antithrombin (AT), protein C, free protein S, tissue plasminogen activator (t-PA), α2-antiplasmin, thrombin-antithrombin complex, and prothrombin fragment 1+2. All variables were assessed before treatment and six months after treatment onset. RESULTS: In the LNG-IUS group, FVIII decreased 10% after six months of use. In the GnRHa group, there was a 6% increase in AT, 29% reduction in D-dimers, and 19% increase in t-PA. The LNG-IUS users exhibited a significantly greater reduction of FVIII than the GnRHa users (LNG-IUS: -6.4 ± 14.3% vs. GnRHa: 4.2 ± 12.3%, p=0.02). The women in the GnRHa group exhibited a greater increase of AT than the LNG-IUS users (LNG-IUS: -0.7 ± 9.5% vs. GnRHa: 6.5 ± 10.1%, p=0.02). CONCLUSION: Both hormonal treatments for endometriosis exhibited no association with a procoagulant profile.

Effect of antiretroviral therapy including lopinavir/ritonavir or efavirenz on etonogestrel-releasing implant pharmacokinetics in HIV-positive women.

OBJECTIVE: Data on the interaction between the etonogestrel (ENG) implant and antiretroviral therapy are lacking. We evaluated the effect of 2 highly active antiretroviral therapy (HAART) regimens (1 including efavirenz and the other ritonavir-boosted lopinavir) on the pharmacokinetic (PK) parameters of an ENG-releasing implant in HIV-positive women. DESIGN: Prospective nonrandomized PK study. METHODS: Forty-five HIV-positive women who desired to use ENG implants were included: 15 had received zidovudine/lamivudine + lopinavir/ritonavir for ≥3 months (LPV/r-based HAART group), 15 had received zidovudine/lamivudine + efavirenz for ≥3 months (EFV-based HAART group), and 15 had not received HAART (non-HAART group). PK parameters were measured using ultra-performance liquid chromatography-mass spectrometry at baseline and 2, 4, 6, 8, 10, 12, 16, 20, and 24 weeks after implant placement. RESULTS: The EFV-based HAART regimen was associated with a reduction in the bioavailability of ENG, which showed decreases of 63.4%, 53.7%, and 70% in the area under the curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of ENG, respectively, compared with the non-HAART group. The LPV/r-based HAART regimen was associated with an increase in ENG bioavailability, which showed 52%, 60.6%, and 33.8% increases in the ENG AUC, Cmax, and Cmin, respectively, compared with the non-HAART group. CONCLUSIONS: The coadministration of EFV decreased the bioavailability of ENG released from the implant, which could impair contraceptive efficacy. However, the coadministration of LPV/r increased the bioavailability of ENG released from the implant, which suggests that this antiretroviral combination does not impair the ENG implant efficacy.

Effects of the etonogestrel-releasing contraceptive implant inserted immediately postpartum on maternal hemostasis: a randomized controlled trial.

INTRODUCTION: The puerperium is the period of highest risk for thrombosis during a woman's reproductive life and it is an important time for initiating an effective contraceptive method in order to increase intergestational interval. Thus, the objective of the present study was to evaluated the effects of the etonogestrel (ENG)-releasing contraceptive implant inserted immediately postpartum on maternal hemostasis markers during the first six weeks of delivery. MATERIALS AND METHODS: Forty healthy women aged 18 to 35 years-old were randomized to receive either the ENG-releasing implant 24-48 h after delivery (implant group; n=20) or nothing (control group) until the sixth postpartum week. Blood samples were collected at 24-48 h and at 6 weeks after delivery, and hemostatic variables, including fibrinogen, coagulation factors, protein C, free protein S, antithrombin, α2-antiplasmin, plasminogen activator inhibitor 1, thrombin-antithrombin complex (TAT), prothrombin fragment (PF)1+2, and D-dimers, as well as normalized activated protein C sensitivity ratio (nAPCsr), thrombin time, activated partial thromboplastin time, and prothrombin time were evaluated. RESULTS: Insertion of the ENG-releasing contraceptive implant did not change the physiological reduction in overall coagulation (TAT and PF1+2) and fibrinolysis (D-dimer) markers, or nAPCsr. Reductions in factors II, VII, X and fibrinogen and increases in factor V were greater in the control than in the implant group. Clotting factors remained within normal limits throughout the study. CONCLUSION: The ENG-releasing contraceptive implant inserted immediately postpartum did not have negative effects on physiological variations of the hemostatic system during the first 6 weeks postpartum.

Oral contraceptive containing chlormadinone acetate and ethinylestradiol reduces plasma concentrations of matrix metalloproteinase-2 in women with polycystic ovary syndrome.

Biochemical markers of cardiovascular disease, including matrix metalloproteinases (MMPs), are altered in women with polycystic ovary syndrome (PCOS), with many of these alterations thought to be due to excess androgen concentrations. Despite oral contraceptives (OCs) being the first-line pharmacological treatment in women with PCOS and the importance of MMPs in many physiological conditions and pathological states, including cardiovascular diseases, no study has yet evaluated whether OCs alter plasma concentrations of MMPs. We therefore assessed whether treatment with an OC containing the anti-androgenic progestogen alters MMP profiles in women with PCOS. We analysed 20 women with PCOS who wanted hormonal contraception (OC-PCOS group), 20 ovulatory women who required hormonal contraception (OC-control group) and 20 ovulatory women who wanted non-hormonal contraception (non-OC-control group). OC consisted of cyclic use of 2 mg chlormadinone acetate/30 µg ethinylestradiol for 6 months. Plasma concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured by gelatin zymography or enzyme-linked immunoassays. OC treatment for 6 months significantly reduced plasma MMP-2 concentrations in the OC-control and OC-PCOS groups and TIMP-2 and TIMP-1 concentrations levels in the OC-control group (all p < 0.05), but had no effects on MMP-9 concentrations or on MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in any group (all p > 0.05). These findings indicated that long-term treatment with an OC containing chlormadinone acetate plus ethinylestradiol reduced plasma MMP-2 concentrations in both healthy and PCOS women. As the latter have imbalances in circulating matrix MMPs, treatment of these women with an OC may be beneficial.

Imbalanced circulating matrix metalloproteinases in polycystic ovary syndrome.

Altered levels of matrix metalloproteinases (MMPs) may reflect relevant pathogenetic mechanisms of disease conditions. The objective of this study was to compare the plasma levels of MMPs and tissue inhibitors of MMPs (TIMPs) in polycystic ovary syndrome (PCOS) patients with those found in healthy ovulatory controls and to examine whether the levels of these biomarkers are associated with clinical and biochemical features of this syndrome. Sixty-five healthy ovulatory subjects (controls) and 80 patients with PCOS were include in this study. MMP-2, MMP-8, MMP-9, TIMP-1, TIMP-2 concentrations were measured in plasma samples by gelatin zymography or enzyme-linked immunoassays. MMP-2, MMP-8, MMP-9, and TIMP-1 levels were similar in PCOS patients and in healthy controls (P > 0.05). PCOS patients had lower plasma TIMP-2 levels than healthy controls (P < 0.05). We found higher MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in PCOS patients than in healthy controls (all P < 0.05). Testosterone levels correlated positively with the MMP-9/TIMP-1 ratio and negatively with TIMP-2 levels (r = 0.26, P < 0.01 and r = -0.21, P = 0.02, respectively). In addition, only testosterone was an independent predictor of TIMP-2 levels (estimate = -0.35, P = 0.04) and the MMP-9/TIMP-1 ratio (estimate = 0.01, P = 0.04). We found evidence indicating that the balance between MMPs and TIMPs in women with PCOS is altered, probably due to androgen excess found in these women.

Controlled ovarian stimulation with exclusive FSH followed by stimulation with hCG alone, FSH alone or hMG.

OBJECTIVE: To assess if low-dose hCG is similar to hMG and to rFSH in the late follicular phase. STUDY DESIGN: In a prospective randomized controlled trial, 51 patients undergoing controlled ovarian stimulation received ovarian priming with rFSH and then received hCG (200 IU/day) (hCG group, n=17), hMG (225 IU/day) (hMG group, n=17) or rFSH (200 IU/day) (FSH group, n=17) in the late stage of follicular development. Parameters of follicular response and serum estradiol, progesterone and testosterone levels were assessed. RESULTS: Pre-ovulatory ovarian follicle occurrence and length of treatment were similar among the three treatment groups. Serum progesterone level on the day of pre-ovulatory hCG was significantly higher in the hCG group than in the hMG or rFSH group. Clinical pregnancy rates were similar for all groups. The total cost of treatment was significantly lower for the hCG group than for the groups supplemented with hMG or rFSH. CONCLUSIONS: LH in the form of low-dose hCG during the late follicular phase induced the same follicular pattern as hMG and rFSH after ovulation induction. The procedure using hCG produced pregnancy rates similar to those obtained using hMG and rFSH, even though the patients showed higher serum progesterone levels on the hCG day.