Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta-Analysis Approach.

Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m2 ) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG's efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m2 : 50-65%; obese women: 70-75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2-1.30 and 1.80-2.10, respectively, in women with BMI < 25 kg/m2 (incidence rate ratios (IRRs): 1.7-2.2), whereas it ranged from 1.6-1.80 and 2.40-2.85 in obese women (IRR: 2.2-3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.

Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia.

OBJECTIVES: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. DESIGN: Multicenter, open-label, phase 3 trial. SETTING: Sixty-nine sites in Europe and Russia. POPULATION: Sexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m2 . METHODS: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary. MAIN OUTCOME MEASURES: Pearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs. RESULTS: A total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events. CONCLUSION: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile. TWEETABLE ABSTRACT: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Pilot Data on the Feasibility And Clinical Outcomes of a Nomegestrol Acetate Oral Contraceptive Pill in Women With Premenstrual Dysphoric Disorder.

Background: Up to 80% of reproductive-aged women experience premenstrual symptoms. Premenstrual Dysphoric Disorder (PMDD) is a severe form, affecting 2-5% of women. Combined oral contraceptive pills (COCPs) are used in the treatment of PMDD. Clinical practice suggests that a newer COCP containing nomegestrol acetate (2.5mg) and 17-beta estradiol (1.5mg), may be a suitable treatment for mood symptoms in PMDD. Materials and Methods: This was a clinical follow-up feasibility study of women who had attended the Monash Alfred Psychiatry research centre, Women's Mental Health Clinic, with a diagnosis of PMDD. 67% of the sample also had concurrent cPTSD, 29% co-morbid anxiety, and 20% depression. They were recommended treatment with nomegestrol acetate/17-beta estradiol. Eligible women were contacted by telephone to answer a questionnaire to assess women's subjective response to nomegestrol acetate/17-beta estradiol, acceptability and the Depression, Anxiety and Stress Scale-21 (DASS-21) after being recommended nomegestrol acetate/17-beta estradiol. The paired-sample t-test was used to determine if there were any statistically significant differences in the DASS-21 scores over the study observation period (before and after taking nomegestrol acetate/17-beta estradiol). Results: 35 (74.5%) women reported a subjective positive mood response to nomegestrol acetate/17-beta estradiol, 31 (63.3%) adhered to the medication, and only 10 (20.4%) women reported side effects as the main reason for discontinuing nomegestrol acetate/17-beta estradiol. There were statistically significant reductions (p<0.05) in the overall DASS-21 scores from before women commenced nomegestrol acetate/17-beta estradiol and after commencement of treatment. Conclusions: This preliminary study supports the acceptability and effectiveness of nomegestrol acetate/17-beta estradiol as a treatment for mood symptoms in PMDD. Further research, particularly a randomized controlled trial, is required to elucidate the effect of nomegestrol acetate/17-beta estradiol treatment on mood in PMDD.

An endocrine perspective on menstrual suppression for adolescents: achieving good suppression while optimizing bone health.

Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.

Efficacy of combined oral contraceptives for depressive symptoms and overall symptomatology in premenstrual syndrome: pairwise and network meta-analysis of randomized trials.

OBJECTIVE: Combined oral contraceptives are often considered a treatment option for women with premenstrual syndrome or premenstrual dysphoric disorder also seeking contraception, but evidence for this treatment is scarce. We aimed to determine (1) the level of evidence for the efficacy of combined oral contraceptives in managing premenstrual depressive symptoms and overall premenstrual symptomatology and (2) the comparative efficacy of combined oral contraceptives (the International Prospective Register of Systematic Reviews registration number CRD42020205510). DATA SOURCES: We searched Cochrane Central Register of Controlled Trials, PubMed, Web of Science, PsycINFO, EMCare, and Embase from inception to June 3, 2021. STUDY ELIGIBILITY CRITERIA: All randomized clinical trials that evaluated the efficacy of combined oral contraceptives in women with premenstrual syndrome or premenstrual dysphoric disorder were considered eligible for inclusion in this meta-analysis. STUDY APPRAISAL AND SYNTHESIS METHODS: A random effect Bayesian pairwise and network meta-analysis was conducted with change in premenstrual depressive symptoms and overall premenstrual symptomatology between baseline and 3 cycles as outcome. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Of 3664 records, 9 eligible trials were included that studied 1205 women with premenstrual syndrome or premenstrual dysphoric disorder (mean age per study range, 24.6-36.5 years). The pairwise meta-analysis revealed that combined oral contraceptives were more efficacious than placebo in treating overall premenstrual symptomatology (standardized mean difference, 0.41; 95% credible interval, 0.17-0.67), but not premenstrual depressive symptoms specifically (standardized mean difference, 0.22; 95% credible interval, -0.06 to 0.47). However, none of the combined oral contraceptives were more effective than each other in reducing premenstrual depressive symptoms and overall premenstrual symptomatology. CONCLUSION: Combined oral contraceptives may improve overall premenstrual symptomatology in women with premenstrual syndrome or premenstrual dysphoric disorder, but not premenstrual depressive symptoms. There is no evidence for one combined oral contraceptive being more efficacious than any other.

Effects of Lemborexant on the Pharmacokinetics of Oral Contraceptives: Results From a Phase 1 Drug-Drug Interaction Study in Healthy Females.

Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug-drug interaction study was conducted. This single-center, open-label, fixed-sequence study examined potential drug-drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18-44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady-state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment.

Adding Combined Oral Contraceptives or Metformin to Laser Treatment in Polycystic Ovarian Syndrome Hirsute Patients.

BACKGROUND: Hirsutism is estimated to affect 10% to 20% of females, provoking significant psychological damage and social embarrassment. Polycystic ovary syndrome is a major cause of hirsutism. AIM: Assessing the impact of adding combined oral contraceptives (COCs) or metformin to laser hair removal on the quality of life of polycystic ovarian syndrome (PCOS) patients with hirsutism. METHODOLOGY: One-hundred-fifty PCO patients diagnosed with hirsutism were included in this study. Patients were randomized into three groups: group 1 received laser hair removal alone, group 2 received metformin and laser hair removal, and group 3 received COCs and laser hair removal. A diode laser with a wavelength of 810 nm was used for hair removal in all patients according to a protocol of 6 monthly sessions followed by another two sessions after three and six months. Patients were assessed using a visual analog scale (VAS) and Dermatology Life Quality Index (DLQI) and a customized questionnaire (Hirsutism Life Quality Index; HLQI). RESULTS: All patients showed a significant improvement in both quality indices (DLQI and HLQI) after treatment relative to pretreatment. Group 3 showed significantly better improvements when compared with group 2 and group 1. At three and six months, group 3 showed non-significantly better DLQI and HLQI as compared with at zero months. On the other hand, group 2 patients displayed significant worsening of both DLQI and HLQI scores at three months, with subsequent improvements again at six. Finally, group 1 patients showed nonsignificant worsening at three months, and significant worsening at 6 months. CONCLUSION: Combining hormonal treatment with laser hair removal can achieve greater hair reduction, significant improvements in patients' QOL, and better maintenance as compared with when combining metformin with laser hair removal or conducting alone. J Drugs Dermatol. 2021;20(3):302-306. doi:10.36849/JDD.5652.

Effect of oral contraceptives on total and bioavailable 25-hydroxyvitamin D.

Studies show an increase in circulating levels of 25-hydroxyvitamin D [25(OH)D] in women using combined oral contraceptives (COCs). 25(OH)D is a quantitatively important metabolite and widely used clinical marker of vitamin D status and is regulated by vitamin D binding protein (VDBP). However, studies have not identified the type of formulations used by the women, and there are no data on the effect of progestins on 25(OH)D levels. Our study objective was to compare the effects of two COC formulations [ethinyl estradiol (EE)/norethindrone acetate (NETA) vs. EE/levonorgestrel (LNG)] as well as LNG alone on total and bioavailable (free plus albumin-bound) 25(OH)D levels in serum samples collected at baseline, mid treatment, and end of treatment. Total 25(OH)D and VDBP were measured by immunoassay, and bioavailable 25(OH)D was calculated. The results show that with the EE/NETA formulation, total and bioavailable 25(OH)D and VDBP levels increased non-significantly by 7.4 %, 14.9 %, and 10 %, respectively, from baseline to end of treatment. In contrast, the corresponding changes with EE/LNG showed an increase of 4.4 % in total 25(OH)D but a significant decrease of 18.2 % in bioavailable 25(OH)D and increase of 19.1 % in VDBP. When LNG was administered alone, no significant changes were observed in total and bioavailable 25(OH)D or VDBP levels during the course of treatment. Our findings show considerably different effects on total and bioavailable 25(OH)D levels, as well as VDBP levels, with different oral contraceptive formulations. LNG may have a suppressive effect on VDBP, similar to its well-known androgenic effect on SHBG. Further studies are needed to determine the effect of hormonal contraceptive formulations on vitamin D status and its potential impact on women's health.

Tolosa-Hunt syndrome relapse during pregnancy following chronic intake of combined oral contraceptives.

Tolosa-Hunt syndrome (THS) is a rare syndrome of painful ophthalmoplegia secondary to an idiopathic granulomatous inflammation affecting the cavernous sinus, superior orbital fissure or orbit. Pregnancy and pregnancy-related hormones have been identified as potential triggers. A 39-year-old gravida-2 para-1 woman with prior chronic intake of combined oral contraceptives (COC) suffered two episodes of painful ophthalmoplegia-the first event with spontaneous remission and the relapse occurring during pregnancy and with complete resolution following steroid treatment. MRI revealed a postinflammatory mass at the junction of the left orbital apex and anterior cavernous sinus, supporting the diagnosis of THS. To our knowledge, this is the first report of a THS relapse occurring during pregnancy following a chronic history of COC intake. This case adds to the growing evidence supporting the relationship between immune and hormonal factors that may be present during pregnancy and the disease pathogenesis of THS.

Long-term use of spironolactone for acne in women: A case series of 403 patients.

BACKGROUND: There are limited data regarding the long-term outcomes of spironolactone use for women with acne and its effect on truncal acne. OBJECTIVE: To comprehensively describe outcomes of patients treated with spironolactone in routine clinical practice, including long-term outcomes. METHODS: We performed a retrospective case series of 403 adult women treated for acne with spironolactone at an academic medical center between 2008 and 2019. Rates of objective, as assessed by Comprehensive Acne Severity Scale scores, and subjective acne clearance were evaluated, as well as rates of treatment discontinuation, dosage changes, and drug survival. Logistic regression was used to assess for association between incidence of menstrual adverse effects and combined oral contraceptive use. RESULTS: As evaluated by Comprehensive Acne Severity Scale scores, at the first follow-up, 75.5%, 84.0%, and 80.2% of patients with available data had reduction or complete clearance of acne on the face, chest, and back, respectively. The mean drug survival was 470.7 days. Menstrual adverse effects were less common among those using combined oral contraception (odds ratio, 0.23; 95% confidence interval, 0.11-0.50). LIMITATIONS: This study was conducted at a single academic medical center. CONCLUSIONS: Spironolactone improves clinical outcomes and is well tolerated for many adult women with acne using it for an extended duration.

Comparison of dienogest versus combined oral contraceptive pills in the treatment of women with adenomyosis: A randomized clinical trial.

OBJECTIVE: To compare the efficacy and safety of dienogest with combined oral contraceptives (COCs) for treating adenomyosis-associated symptoms. METHODS: This was a randomized clinical trial including women with symptomatic adenomyosis conducted from March 1, 2019 to August 1, 2020 at Assiut Woman's Health Hospital, Egypt. Participants were randomly assigned to the dienogest group or COCs group. The primary outcome was the level of adenomyosis-associated pain from before to 6 months after treatment measured by a visual analog scale (VAS). Changes in the uterine bleeding pattern, uterine volume, and uterine artery blood flow were also reported. RESULTS: The VAS score of pain was significantly decreased in both groups; however, the decreased rate was more pronounced in the dienogest group (3.21 ± 1.18) in comparison with the COCs group (4.92 ± 1.22). Bleeding pattern was improved greatly; uterine volume and uterine artery blood flow decreased significantly in the dienogest group. However, women in the dienogest group reported a higher rate of side effects. CONCLUSION: Dienogest and COCs are effective in treating adenomyosis-associated symptoms after 6 months of use but dienogest is more effective. The decrease in uterine volume and uterine artery blood flow may be the cause of the treatment effect. Dienogest carries a higher risk of side effects. CLINICAL TRIAL: gov: NCT03890042.

Options for Prevention and Management of Menstrual Bleeding in Adolescent Patients Undergoing Cancer Treatment: ACOG Committee Opinion, Number 817.

ABSTRACT: Obstetrician-gynecologists frequently are consulted either before the initiation of cancer treatment to request menstrual suppression or during an episode of severe heavy bleeding to stop bleeding emergently. Adolescents presenting emergently with severe uterine bleeding usually require only medical management; surgical management rarely is required. Surgical management should be considered for patients who are not clinically stable, or for those whose conditions are not suitable for medical management or have failed to respond appropriately to medical management. When used continuously, combined hormonal contraceptives are effective for producing amenorrhea, although complete amenorrhea cannot be guaranteed. The risk of venous thromboembolism in patients with cancer is compounded by multiple factors, including presence of metastatic or fast-growing, biologically aggressive cancers; hematologic cancers; treatment-related factors such as surgery or central venous catheters; and the number and type of comorbid conditions. Although as a group, patients undergoing cancer treatment are at elevated risk of venous thromboembolism compared with the general population, this risk may be extremely elevated for certain patients and existing guidance on risk stratification should be consulted. The decision to use estrogen in patients with cancer should be tailored to the individual patient after collaborative consideration of the risk-benefit ratio with the patient and the health care team; the patient should be closely monitored for known adverse effects such as liver toxicity and venous thromboembolism.

Hormonal contraception and risk of STIs and bacterial vaginosis in South African adolescents: secondary analysis of a randomised trial.

OBJECTIVES: Young women in sub-Saharan Africa are at high risk of STIs and unintended pregnancies, yet hormonal contraceptive (HC) use may affect STI risk. We compared the influence of three HCs on the incidence and prevalence of STIs and bacterial vaginosis (BV) in South African adolescents. METHODS: One hundred and thirty adolescents between 15 and 19 years were randomised to the injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) (Triphasil or Nordette) or a combined contraceptive vaginal ring (CCVR; NuvaRing) for 16 weeks (clinicaltrials.gov/NCT02404038). Vaginal samples were collected at baseline and 16 weeks post contraceptive initiation for STI and BV testing. RESULTS: In an intention-to-treat analysis, no significant differences in BV prevalence were found between study arms. The overall incidence of any STI at follow-up was high: 16.2% in the COC arm; 25.7% in the Net-En arm; and 37.1% in the CCVR arm. The incidence rate (IR) of any STI was similar between Net-En (IR 0.74 (95% CI 0.34 to 1.41)) and the oestrogen-containing contraceptives (IR 0.78 (95% CI 0.47 to 1.22)). A lower IR of Chlamydia trachomatis (incidence rate ratio (IRR) 0.68 (95% CI 0.19 to 1.99)) and Neisseria gonorrhoeae (IRR 0.25 (95% CI 0.01 to 1.35)) but a higher IR of Mycoplasma genitalium (IRR 16.0 (95% CI 2.96 to 400)), was observed in the Net-En arm compared with the oestrogen-containing contraceptives, although the overall incidence of M. genitalium was low (4.7%). In an exploratory analysis, the risk of any STI and N. gonorrhoeae was lower in the COC arm compared with CCVR. A per-protocol analysis yielded similar results. CONCLUSION: Our results suggest that use of Net-En may be associated with increased risk of M. genitalium compared with oestrogen-containing contraceptives but not with overall STI risk. COC use may decrease STI risk relative to CCVR.

Hormonal contraception alters vaginal microbiota and cytokines in South African adolescents in a randomized trial.

Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15-19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation.

A safety evaluation of current medications for adult women with the polycystic ovarian syndrome not pursuing pregnancy.

INTRODUCTION: The polycystic ovary syndrome (PCOS) is a very prevalent disorder in premenopausal women. Cardiovascular risk factors cluster in these patients, raising concern about the safety of the drugs commonly used to ameliorate symptoms of androgen excess in in this population at risk of cardiovascular morbidity. AREAS COVERED: This review summarizes the clinical efficacy and safety profiles of drugs commonly used for the management of hyperandrogenic symptoms and endometrial protection in adult women with PCOS who do not seek pregnancy. EXPERT OPINION: Antiandrogenic drugs usually used in adult women with PCOS carry a low risk of severe side effects. In spite of the cardiovascular risk profile of women with PCOS, and that individualized risk assessment is of paramount importance, there is no solid evidence supporting that the use of combined oral contraceptives in these women increases the risk of cardiovascular or thromboembolic events compared with the general population. However, virtually all these drugs are used in an off-label fashion. Large, high-quality studies addressing the long-term safety of pharmacological treatments in women with PCOS are definitely needed.

Comparative pharmacokinetic analysis of levonorgestrel-releasing intrauterine systems and levonorgestrel-containing contraceptives with oral or subdermal administration route.

OBJECTIVE: To compare systemic exposure to levonorgestrel (LNG) released from commercially available intrauterine systems (IUSs), a subdermal implant, and oral contraceptives. METHODS: An integrated population pharmacokinetic (popPK) analysis of data from over 3400 individuals in ten clinical studies with six different LNG-releasing contraceptives (four long-acting reversible contraceptives [LARCs: LNG-IUS 8, 12, and 20, initially releasing LNG 14, 17.5, and 20 µg/day, a subdermal implant initially releasing LNG 100 µg/day according to label]; progestin-only pill [POP: LNG 30 µg/day]; and combined oral contraceptive [COC] pill [LNG 100 µg/day and ethinylestradiol 20 µg/day]), was conducted to generate a popPK model. LNG release rates, and total and unbound serum/plasma LNG concentrations with LARCs were estimated over the indicated period of use; maximum (Cmax) and average (Cav) serum LNG concentrations were estimated at steady state for oral contraceptives. Influence of body weight on LNG PK was also investigated. RESULTS: Serum LNG concentration with LARCs increased with increasing daily LNG release rate, being lowest with LNG-IUS 8, higher with LNG-IUS 12 and LNG-IUS 20, and highest with the subdermal implant (1.7-2.1-times that with LNG-IUS 20). Compared with early serum LNG concentrations with LNG-IUS 20, Cav and Cmax were 1.7- and 4.5-fold higher with POP, and 8.6- and 18-fold higher with COC. Total LNG bioavailability was >97% for the LNG-IUSs and 66-80% with other contraceptives. Serum/plasma LNG concentrations decreased with increasing body weight. CONCLUSIONS: Among the contraceptives examined, COC had the highest and LNG-IUSs the lowest systemic exposure to LNG. Systemic LNG concentration was inversely correlated to body weight.

An open-label, randomized crossover study to evaluate the acceptability and preference for contraceptive options in female adolescents, 15 to 19 years of age in Cape Town, as a proxy for HIV prevention methods (UChoose).

INTRODUCTION: Young women in Southern Africa have extremely high HIV incidence rates necessitating the availability of female-controlled prevention methods. Understanding adolescent preference for seeking contraception would improve our understanding of acceptability, feasibility and adherence to similar modes of delivery for HIV prevention. METHODS: UChoose was an open-label randomized crossover study over 32 weeks which aimed to evaluate the acceptability and preference for contraceptive options in healthy, HIV-uninfected, female adolescents aged 15 to 19 years, as a proxy for similar HIV prevention methods. Participants were assigned to a contraceptive method for a period of 16 weeks in the form of a bi-monthly injectable contraceptive, monthly vaginal Nuvaring® or daily combined oral contraceptive (COC) and then asked to state their preference. At 16 weeks, participants crossed over to another contraceptive method, to ensure that all participants tried the Nuvaring® (least familiar modality) and additionally, either the injection or COC. Primary outcomes were contraceptive acceptability and preference. At the end of the 32 weeks they were also asked to imagine their preference for an HIV prevention modality. Secondary endpoints included changes in sexual behaviour, contraceptive adherence and preference for biomedical and behavioural HIV prevention methods. RESULTS: Of the 180 participants screened, 130 were enrolled and randomized to the Nuvaring® (n = 45), injection (n = 45) or COC (n = 40). Significantly more Nuvaring® users (24/116; 20.7%) requested to change to another contraceptive option compared to injection (1/73; 1.4% p = 0.0002) and COC users (4/49; 8% p = 0.074). Of those that remained on the Nuvaring® , adherence was significantly higher than to COC (p < 0.0001). Significantly more injection users (77/80; 96.3%) thought this delivery mode was convenient to use compared to Nuvaring® (74/89; 83.1%; p = 0.0409) or COC (38/50; 76.0%; p = 0.0034). Overall, the preferred contraceptive choice was injection, followed by the ring and lastly the pill. CONCLUSIONS: Adherence to daily COC was difficult for adolescents in this cohort and the least favoured potential HIV prevention option. While some preferred vaginal ring use, these data suggest that long-acting injectables would be the preferred prevention method for adolescent girls and young women. This study highlights the need for additional options for HIV prevention in youth.

Hormonal Contraceptives and the Risk of Venous Thrombosis.

The risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE), the androgenic progestogens are better able to counteract the EE-induced stimulation of liver proteins and hence are associated with a twofold decreased risk of VT compared with non- or antiandrogenic progestogens, which exert limited counteraction of EE. Because EE is responsible for the increased risk, novel estrogens such as estradiol were developed and seem to have a lower risk of VT than EE. Besides COCs, there are other methods of hormonal contraceptives, such as progestogen-only contraceptives, which do not increase VT risk, except for injectables. Other nonoral contraceptives are combined vaginal rings and patches. There is insufficient evidence regarding the risk of VT associated with these two methods compared with COCs. The increased risk associated with COCs is more pronounced in women with inherited thrombophilia. In these women, the progestogen levonorgestrel seems to be associated with the lowest risk of VT. Currently, there are no studies that have investigated the risk of VT in women who switch COCs. We hypothesize that switching COCs, even when switching from a high- to a low-risk COC, increases the risk of VT. Finally, risk prediction models in women who use COCs are lacking. Since there is a large number of VT cases associated with COC use, it is important to identify women at risk of VT and advise them on alternative contraception methods.